Anti-fungal formulation

ABSTRACT

Provided herein are compositions and formulations comprising an antifungal agent. Pharmaceutical compositions comprising luliconazole in an amount effective for the treatment of onychomycosis are provided. Also provided are methods for treating dermatomycoses and onychomycosis using the compositions and formulations.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Nos. 61/152,658, filed Feb. 13, 2009 and 61/162,661, filedMar. 23, 2009, the disclosures of which are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present application relates to pharmaceutical compositions andformulations that may be used for anti-fungal treatments including, butnot limited to, dermatomycoses and onychomycosis.

BACKGROUND OF THE INVENTION

A number of imidazole antimycotic agents are under investigation or areused for the treatment of dermatomycoses (an infection of the skincaused by dermatophytes or other fungi) or onychomycosis (a fungalinfection of the nail plate and/or nail bed). One such antimycotic agentapproved and launched in Japan for cutaneous mycosis such as Tineapedis, tinea corporis and tinea cruris as well as Candidiasis and Tineaversicolor infection is luliconazole (Lulicon® Cream and Solution 1%).

The compound luliconazole is represented by the formula (I):

Luliconazole is a compound screened from analogues of its predecessorlanoconazole, which has been clinically used for the treatment ofdermatomycoses. It is believed that luliconazole produces its antifungaleffect by inhibiting the synthesis of ergosterol, which is a constituentof the cell membrane of fungi. The antifungal activity of luliconazolewas recently tested against clinically important dermatomycotic fungiand compared to other representative antifungal reference drugs.Luliconazole demonstrated greater potency against Trichophyton rubrum,Trichophyton mentagrophytes and Trichophyton tonsurans than thereference drugs, such as allylamine (terbinafine), thiocarbamate(liranaftate), benzylamine (butenafine), morpholine (amorolfine), andazoles (ketoconazole, clotrimazole, neticonazole, miconazole andbifonazole). Koga et al., Med. Mycol. (2008) 1-8.

The concentration of luliconazole in a stable cream is found in thecommercial product Lulicon® at 1% by weight. Creams and other liquidformulations containing luliconazole have been described as having about0.5% to about 5% by weight luliconazole. See, e.g., U.S. PatentPublication Nos. US2009/0137651, published May 28, 2009; US2009/0076109,published Mar. 19, 2009; and US2009/0030059, published Jan. 29, 2009.Creams and other liquid formations containing greater than 5%luliconazole are known to be unstable and difficult to solubilize,resulting in crystallization or precipitation of the compound out ofsolution. Nonetheless, there remains a need for such formulations, e.g.,for use in the treatment of dermatomycoses and onychomycosis.

Tinea pedis, also known as athlete's foot, is the most common of thedermatomycoses, affecting up to 10 percent of the general population.However, onychomycosis, which accounts for up to 50% of all naildiseases and affects approximately 35 million people in the U.S. alone,is much more difficult to treat than Tinea pedis, for several reasons,such as the site of infection, time required to regenerate healthy nail,and the composition of a nail as compared to the skin. Dandah, M. J. etal., (2006) U.S. Dermatology Review 1-4. As a result, formulations thatare sufficient in the treatment of Tinea pedis are not generallysufficient for the treatment of onychomycosis.

The site of fungal infection in onychomychosis makes its treatmentparticularly challenging. Distal subungual onychomycosis (DSO), which isthe most common form of onychomycosis, is characterized by fungalinvasion of the nail bed and underside of the nail plate beginning atthe hyponychium. Clinical findings associated with DSO include naildiscoloration (yellowing or other discoloration such as the presence ofblack or brown color), thickening, subungual debris and loss ofattachment of the nail plate to the nail bed. The nail may also becomefriable and crumble away. DSO can cause extreme nail disfigurement andoften results in pain. Treatment of the infected region with a topicalpharmaceutical composition requires the composition to deliver atherapeutically effective amount of the active agent through the nail inorder to reach the site of infection. The only U.S. Food and Drug Agencyapproved topical treatment for onychomycosis is ciclopirox (Penlac®,Dermik) an 8% topical solution applied as a nail lacquer. In De Berker,N. Engl. J. Med. (2009) 360: 2108-16, the mycologic cure for DSO usingPenlac daily for 48 weeks was reported to be 28 to 36%. However, a clearnail was achieved in only 7% of cases. Amorolfine (Loceryl®, Galderma)is another topical therapy that has long treatment times and low curerates, likely as a result of poor drug penetration through the nail. DeBerker, supra. Topical therapeutics for onychomycosis thus fail toprovide optimal treatment of the infection site. Orally administereddrugs are an alternative to topical treatments for onychomycosis, buthave their own disadvantages, including prolonged systemic exposure toan active agent when only a specific site is infected. Ketoconazole(Nizoral®, Janssen-Cilag) was the first oral imidazole introduced forthe treatment of onychomycosis in the 1980s. However, due tohepatotoxicity its use is now restricted to nail infections that havefailed to respond to other therapies. Griseofulvin (Grisovin®, GlaxoWelcome) is an oral therapeutic that has been available since the 1950swhich results in low cure and high relapse rates. Elewski, B. E.,Clinical Microbiology Reviews (1998) 11:415-429. The newer oralanti-fungals, terbinafine (Lamisil®) and itraconazole (Sporanox®) areeffective in the treatment of onychomycosis with mycological cure ratesof 70-80% and treatment periods of 12-16 weeks. However, even in thenewer oral anti-fungals, the percentage of patients exhibiting bothmycological cure and clinical cure remain low. For example, in a studyof patients being treated for onychomycosis of the toenail withLamisil®, only 38% of patients treated demonstrated both mycologicalcure (simultaneous occurrence of negative KOH plus negative culture) andclinical cure (0% nail involvement). See Lamisil® Package Insert. In astudy of patients being treated for onychomycosis of the toenail withSporanox®, only 14% of patients treated demonstrated both mycologicalcure and clinical cure. See Sporanox® Package Insert. These drugs alsohave significant side effects and interact with many medications, whichlimits their use. For example, liver failure requiring liver transplantor resulting in death have occurred in patients, with and withoutpreexisting liver disease, taking oral Lamisil® for the treatment ofonychomycosis. In addition, Lamisil® is known to inhibit CYP450 2D6isozyme. Drugs that are predominately metabolized by the CYP450 2D6isozyme include tricyclic antidepressants, selective serotonin reuptakeinhibitors, beta-blockers, antiarrhyhmics class 1C and monoamino oxidaseinhibitors type B, and individuals who are taking one or more of thesemedications concurrently with Lamisil® must be carefully monitored andmay require a reduction in dosage of such drugs. Sporanox® has beenassociated with cases of serious hepatotoxicity, including liver failureand death, with certain instances occurring in individuals havingneither pre-existing liver disease or a serious underlying medicalcondition. Sporanox®, which is an inhibitor of CYP3A4, is alsocontraindicated in patients with evidence of ventricular dysfunction,such as patients with congestive heart failure and in patients takingcisapride, pimozide, levacetylmethadol (levomethadyl), or quinidineconcomitantly with Sporanox® and/or other CYP3A4 inhibitors. Thus, oraltherapies do not provide sufficient or effective cure rates, areassociated with series adverse side affects and limited in theirapplication. A significant unmet medical need remains for an effectivetreatment of onychomycosis. A treatment that has fewer and/or lesssevere side effects than those associated with current therapies wouldbe particularly beneficial.

Since some onychomycosis infections may require up to a year oftreatment for healthy, non-infected nail to fully regrow, the activeagent must be present at the infected site in therapeutic concentrationslong enough to effect a cure. Such agents should also prevent relapseand re-infection after discontinuation of therapy, have minimal sideeffects and exhibit an acceptable safety profile. Chronic administrationof either a topical or oral treatment is therefore required, and willtypically last for the period of time required for new, healthy nail toregrow, which can vary on an individual basis. Treatment periods foronychomycosis generally start at several weeks to several months longand last up to a year. Chronic administration of a topical or oralantifungal drug presents unique toxicity concerns. For example, even ifan active agent is deemed safe for chronic use, its topicaladministration must be carried out in a manner that formulates theactive agent at a desired concentration and where the carrier itself issafe for chronic administration to the nail. Chronic administration of atopical composition also requires patient compliance, which can becompromised if the treatment regimen is difficult or otherwiseundesirable. For example, patient compliance in the treatment ofonychomycosis is more likely to be compromised if the pharmaceuticalcomposition has any one or more of the following features: is sticky orhas an unpleasant texture, irritates the nail or surrounding skin,leaves an uncomfortable film on the nail, is messy to apply (e.g., whenits application results in ‘run-off’ in which the composition does notstay on the nail and uncontrollably rolls or seeps off the nail and ontothe surrounding skin), has a bad odor, requires periodic (e.g., weekly)removal of resulting film or lacquer, and the like. Thus, in the contextof chronic administration of an active agent to the nail, the safety andperformance characteristics of the pharmaceutical composition containingthe active agent are highly important. Chronic administration of an oraldrug also requires patient compliance. In addition, chronicadministration of an oral drug in the treatment of onychomycosis resultsin prolonged systemic exposure to the active agent, which can haveadverse health consequences such as undesired drug-drug interactionswith existing medications and toxicity concerns, both of which cangreatly limit use in a large portion of the patient population (e.g., inelderly patients who are more susceptible to onychomycosis and also whoare more likely to be on a daily regimen of other pharmaceuticalagents). Patients taking oral antifungal medications should also haveperiodic laboratory evaluations to monitor liver and blood cellfunction. Elewski, B. E., supra.

Onychomycosis affects toenails substantially more than fingernails andtoenails are approximately twice as thick as fingernails. The reportedprevalence of toenail onychomycosis in the Western adult population isapproximately 14% and increases with age. De Berker, supra. The nailplate, through which an active agent must travel to reach the site ofonychomycosis infection, is dense and hard. In addition, the nail plateof a toenail is substantially thicker than the nailplate of afingernail, providing a formidable barrier to the nail bed. In contrastto Tinea pedis treatment, in which the active agent has to pass thethin, elastic and pliable Stratum coreum (the outermost layer of theepidermis) of the skin, treatment of onychomycosis requires an activeagent to pass through the hard, dense and thick nail plate of afingernail or toenail. The natural barrier of a nail provides a harsherenvironment and a much longer diffusion pathway for drug delivery ascompared to treatment applications that only need to penetrate theStratum coreum of the skin, with toenails having about twice thediffusion pathway of fingernails. The physical and chemical differencesbetween the nail and the Stratum coreum account for the unique treatmentchallenges for fungal infections involving the nail, especially thetoenail, which are not shared by fungal infections of the skin.

Factors that contribute to the development of onychomycosis includeadvanced age, diabetes (which reduces circulation to the extremities),history of prior infection, wearing heat- and moisture-retainingfootwear, communal bathing, immunosuppression (e.g., HIV infection, theuse of antibiotics or immunosuppressive drugs), trauma to the nail, useof insufficiently cleaned manicure tools, poor overall health, and warmclimates.

It is estimated that about half of those affected with onychomycosis arenot receiving treatment. Medical News Today, Mar. 21, 2008. However, itis important to treat onychomycosis, as it is an infection and does notresolve spontaneously. The infection may worsen, spread to otheruninfected locations (e.g., other nails or to the surrounding skin) orinfect other individuals. Onychomycosis infections can greatly affect anindividual's quality of life and cause pain and morbidity. Infections ofthe fingernails, which are plainly visible, may be cosmeticallyunacceptable and result in embarrassment, emotional distress, loss ofself-esteem, anxiety and depression. Individuals with moderate to severeonychomycosis may experience limits in manual performance andambulation, loosing their ability to perform many routine tasks.

Current therapies do not sufficiently or effectively meet the challengespresented by onychomycosis. Existing topical therapies for onychomycosishave low mycologic cure rates and poor complete cure rates. They canalso be inconvenient to the user, requiring the daily application of anail laquer and weekly removal of the resulting film. Oral therapies foronychomycosis are assoicated with higher mycologic cure rates thanexisting topical therapies, but these drugs exhibit poor cure rates, arecontraindicated in numerous patient populations and have been associatedwith severe, and even deadly, side effects. Due to the low cure ratesand significant drawbacks to existing therapies, the development of newtopical treatments for onychomycosis is desired. A topical treatmentthat results in high cure rates, provides a clear nail, has minimal sideeffects, and is associated with high patient compliance, is particularlydesired. An effective topical treatment for onychomycosis preferablyaddresses each of the challenges presented by onychomycosis. Thecompositions and formulations described herein provide a significantsolution to this problem and provide additional benefits as providedherein.

The foregoing examples of the related art and limitations are intendedto be illustrative and not exclusive. Other limitations of the relatedart will become apparent to those of skill in the art upon a reading ofthe specification as provided herein.

SUMMARY OF THE INVENTION

In one embodiment of the application, there is provided a stablepharmaceutical composition comprising a luliconazole type antifungalagent or a pharmaceutically acceptable salt thereof wherein theantifungal agent comprises greater than about 5% by weight of thecomposition. In one aspect, the antifungal agent is greater than about7% by weight of the composition. In another aspect, the antifungal agentis greater than about 10% by weight of the composition. In yet anotheraspect, the antifungal agent is from about 5% to about 12.5% by weightof the composition. In one aspect, a pharmaceutical compositiondescribed herein comprises luliconazole in about 5 weight percent toabout 15 weight percent or from about 8 weight percent to about 15weight percent or from about 10 weight percent to about 15 weightpercent or from about 12 weight percent to about 15 weight percent orfrom about 5 weight percent to about 12 weight percent or from about 5weight percent to about 10 weight percent or from about 5 weight percentto about 8 weight percent or from about 8 weight percent to about 12weight percent or from about 9 weight percent to about 11 weightpercent. In another aspect, a pharmaceutical composition comprisesluliconazole in at least about or about any of 5 or 8 or 10 or 12 or 15weight percent.

In one particular aspect, the compositions provided herein are stablefor at least 4 weeks. In another aspect, the compositions are stable forat least 4 weeks at a temperature of about 4° C. The luliconazolecompositions provided herein may exhibit any one or more of thefollowing attributes: (i) the composition remains as a clear solutionwithout evidence of crystal formation upon visual inspection after anyof 1 or 2 or 3 or 4 or 5 or 6 or 12 or 18 or 24 months or more ofstorage at any of 5° C., 25° C. and 40° C.; (ii) the compositioncontains at least about any of 80% or 85% or 90% or 95% of thetheoretical maximum amount of luliconazole after 2 or 4 or 6 months ofstorage at any of 5° C., 25° C. and 40° C.; (iii) the compositioncontains no more than any of 0.2 or 0.3 or 0.5 or 0.75 or 1 weightpercent of the Z form of luliconazole after any of 1 or 2 or 3 or 4 or 5or 6 or 12 or more months of storage at any of 5° C., 25° C. and 40° C.;(iv) the composition contains no more than any of 0.2 or 0.3 or 0.5 or0.75 or 1 or 2 or 3 or 4 or 5 weight percent of the SE form ofluliconazole after any of 1 or 2 or 3 or 4 or 5 or 6 or 12 or moremonths of storage at any of 5° C., 25° C. and 40° C.; (v) thecomposition contains no more than any of 0.5, or 1 or 2 or 3 or 4 or 5combined weight percent of the Z and SE forms of luliconazole after anyof 1 or 2 or 3 or 4 or 5 or 6 or 12 or more months of storage at any of5° C., 25° C. and 40° C.; and (vi) the composition contains at leastabout any of 80% or 90% or 100% or 110% label of luliconazole after anyof 1 or 2 or 3 or 4 or 5 or 6 or 12 or more months of storage at any of5° C., 25° C. and 40° C.

In another aspect, the compositions provided herein comprise at leastone excipient, or alternatively at least two excipients, oralternatively at least three excipients selected from the groupconsisting of an alcohol, a ketone, a polar aprotic solvent and anethylene glycol derivative. In another aspect, the alcohol is benzylalcohol, ethanol or a combination thereof. In yet another aspect, theketone is acetone. In yet another aspect, the polar aprotic solvent ispropylene carbonate. In still yet another aspect, the ethylene glycolderivative is diethylene glycol monoethyl ether (such as Transcutol™ P).In one aspect, the ethanol is from about 35% to about 60% by weight ofthe composition. In another aspect, the benzyl alcohol is from about 1%to about 15% by weight of the composition. In another aspect, theacetone is from about 5% to about 15% by weight of the composition. Inyet another aspect, the diethylene glycol monoethyl ether (such asTranscutol™ P) is from about 5% to about 30% by weight of thecomposition.

In another aspect, the compositions provided herein comprise 10% activeagent, 2% benzyl alcohol, 12% acetone and 25% diethylene glycolmonoethyl ether (such as Transcutol™ P). In another aspect, thecompositions provided herein comprise 12.5% active agent, 4% benzylalcohol, 12% acetone and 25% diethylene glycol monoethyl ether (such asTranscutol™ P). In yet another aspect, the compositions provided hereinfurther comprise a film-forming agent, such as, but not limited tomethylvinyl ether-maleic anhydride (Gantrez). In still yet anotheraspect, the compositions provided herein are formulated as a gel orcream for topical administration.

In one aspect of the above, the antifungal agent is luliconazole of theformula:

or a pharmaceutically acceptable salt thereof.

Luliconazole in the compositions described herein may be present insubstantially pure form (e.g., the composition contains no more than 15%or preferably no more than 10% or more preferably no more than 5% oreven more preferably no more than 3% and most preferably no more than 1%impurity, which impurity in one aspect is a different stereochemicalform of luliconazole, such as the Z or SE forms of luliconazole) or mayalso be present in the context of a racemic or other mixture, e.g.,together with the Z or SE forms of luliconazole.

In one embodiment, the invention provides for a pharmaceuticalcomposition comprising about 5 weight percent to about 15 weight percentluliconazole, an alcohol, a ketone and a polar aprotic solvent. In oneaspect, the alcohol is benzyl alcohol or ethanol. In another aspect, theketone is acetone. In a further aspect, the polar aprotic solvent ispropylene carbonate. In a particular variation, the compositioncomprises two alcohols, which in one embodiment are benzyl alcohol andethanol. In one aspect, the composition may further comprises anethylene glycol derivative, such as an ethylene glycol derivative of theformula HOCH₂CH₂OCH₂CH₂OR where R is an alkyl group having 1 to 6 carbonatoms. Thus, in one aspect the ethylene glycol derivative isdiethyleneglycol monoethyl ether.

In another embodiment, the invention provides for a pharmaceuticalcomposition comprising luliconazole, an ethylene glycol derivative andat least two of an alcohol, a ketone, and a polar aprotic solvent. Inone aspect, the alcohol is benzyl alcohol or ethanol. In another aspect,the ketone is acetone. In a further aspect, the polar aprotic solvent ispropylene carbonate. In a particular variation, the compositioncomprises two alcohols, which in one embodiment are benzyl alcohol andethanol. In one aspect, the composition comprises at least two of benzylalcohol, acetone, propylene carbonate and ethanol. In another aspect,the composition comprises at least three of benzyl alcohol, acetone,propylene carbonate and ethanol. In one such variation, the compositioncomprises benzyl alcohol, acetone and propylene carbonate and whereinthe ethylene glycol derivative, acetone and propylene carbonate whentaken together account for about 40 weight percent to about 45 weightpercent of the composition. In another embodiment, the compositioncomprises at least four of benzyl alcohol, acetone, propylene carbonate,ethanol and where the an ethylene glycol derivative is of the formulaHOCH₂CH₂OCH₂CH₂OR where R is an alkyl group having 1 to 6 carbon atoms.Thus, in one aspect the ethylene glycol derivative is diethyleneglycolmonoethyl ether.

In any of the preceding embodiments, in one aspect the compositioncomprises 0.01 weight percent to about 5 weight percent benzyl alcohol.In another aspect of such embodiments, the composition comprises about 8weight percent to about 15 weight percent luliconazole. In a furtheraspect of such embodiments, the composition further comprises a filmforming agent in from 0.01 weight percent to about 4 weight percent. Inone aspect, the film-forming agent is a maleic anhydride/methyl vinylether copolymer, which in a particular variation is Gantrez® ES-425.

In any of the preceding embodiments, in one aspect the composition issubstantially anhydrous.

In any of the preceding embodiments, in one aspect the composition is aclear solution without evidence of crystal formation upon visualinspection after 6 months of storage at any of 5° C., 25° C. and 40° C.

In any of the preceding embodiments, in one aspect the compositioncomprises at least about 95% of the theoretical maximum amount ofluliconazole after 6 months of storage at any of 5° C., 25° C. and 40°C.

In any of the preceding embodiments, in one aspect the composition is aclear solution without evidence of crystal formation upon visualinspection after 6 months of storage at any of 5° C., 25° C. and 40° C.and wherein the composition contains at least about 95% of thetheoretical maximum amount of luliconazole after 6 months of storage atany of 5° C., 25° C. and 40° C.

In any of the preceding embodiments, in one aspect the compositioneradicates at least 80% of a fungal infection of the nail after 14 daysof treatment, as measured by the recovery of less than 20% of thetheoretical amount of recoverable ATP from the fungus.

In any of the preceding embodiments, in one aspect the composition is aclear solution without evidence of crystal formation upon visualinspection after 6 months of storage at any of 5° C., 25° C. and 40° C.and wherein the composition contains at least about 95% of thetheoretical maximum amount of luliconazole after 6 months of storage atany of 5° C., 25° C. and 40° C.

In any of the preceding embodiments, in one aspect the composition isprovided wherein at least 50 μg/cm² of luliconazole penetrates through a0.5 mm thick nail when 1 μL the composition is applied to the nail oncedaily for 3 days.

In any of the preceding embodiments, in one aspect the composition isfree of an alpha-hydroxycarboxylic acid, NMP and crotamiton. In any ofthe preceding embodiments, in one aspect the composition dries in lessthan about 5 minutes after application to a nail.

Also provided is a pharmaceutical composition, comprising: from about 5weight percent to about 15 weight percent luliconazole; from about 5weight percent to about 25 weight percent acetone; from about 1 weightpercent to about 15 weight percent propylene carbonate; from about 15weight percent to about 35 weight percent of an ethylene glycolderivative of the formula HOCH₂CH₂OCH₂CH₂OR where R is an alkyl grouphaving 1 to 6 carbon atoms; and from 0.01 weight percent to about 6weight percent benzyl alcohol. In one aspect, R is ethyl. In anotheraspect, the composition comprises 2 weight percent to 4 weight percentbenzyl alcohol. In a further aspect, the composition comprises a filmforming agent in from 0.01 weight percent to about 4 weight percent. Inone variation, the film-forming agent is a maleic anhydride/methyl vinylether copolymer, such as the film forming agent Gantrez® ES-425. In onevariation, the composition further comprises ethanol. In anothervariation, the composition comprises from about 35 weight percent toabout 45 weight percent ethanol.

In a particular variation, a pharmaceutical composition is providedwherein the composition comprises from about 9 weight percent to about12.5 weight percent luliconazole; from about 8 weight percent to about15 weight percent acetone; from about 3 weight percent to about 8 weightpercent propylene carbonate; from about 20 weight percent to about 30weight percent of an ethylene glycol derivative of the formulaHOCH₂CH₂OCH₂CH₂OR where R is an alkyl group having 1 to 6 carbon atoms;and benzyl alcohol from 0.01 weight percent to about 5 weight percent.In one such variation, R is ethyl. IN one aspect, the compositioncomprises about 2 weight percent to about 4 weight percent benzylalcohol. In another aspect, the composition further comprises a filmforming agent in from 0.01 weight percent to about 4 weight percent. Inone variation, the film-forming agent is a maleic anhydride/methyl vinylether copolymer, such as the film forming agent is Gantrez® ES-425. Inone variation, the composition further comprises ethanol. In anothervariation, the composition comprises from about 35 weight percent toabout 45 weight percent ethanol.

In one variation, the composition comprises about 10 weight percentluliconazole. In another variation, the composition comprises about 12.5weight percent luliconazole.

In a specific variation, a pharmaceutical composition is provided,wherein the composition comprises about 10 weight percent luliconazole;about 12 weight percent acetone; about 5 weight percent propylenecarbonate; about 25 weight percent of an ethylene glycol derivative ofthe formula HOCH₂CH₂OCH₂CH₂OR where R is ethyl; and about 4 weightpercent benzyl alcohol. In one such variation, the composition furthercomprises a film forming agent in about 1 weight percent. In on aspect,the film-forming agent is a maleic anhydride/methyl vinyl ethercopolymer. In another aspect, the film forming agent is Gantrez® ES-425.In a further variation, the composition comprises ethanol.

Also provided is a method of treating onychomycosis in an individual inneed thereof, comprising contacting the individual's nail with any ofthe preceding pharmaceutical compositions. In one aspect, the method isa method of treating distal subungual onychomycosis. In another aspect,the method is a method of treating onychomycosis of a toenail orfingernail. In one aspect, method comprises contacting the individual'snail with the composition once daily. In one variation, the individualis diabetic, is of an advanced age or is immunocompromised.

Also provided is a method of penetrating a nail with luliconazole in anindividual in need thereof, comprising contacting the individual's nailwith any of the preceding compositions. In one aspect, the methodcomprises administering a composition comprising at least about 10weight percent luliconazole to the individual's nail once daily for atleast three days. In one aspect, the nail is a toenail. In anotheraspect, the nail is a fingernail.

Methods for preparing a pharmaceutical composition comprisingluliconazole are also described. In one aspect, the method comprisescombining luliconazole with an ethylene glycol derivative, an alcohol, aketone, a polar aprotic solvent. In one variation, the ethylene glycolderivative of the formula HOCH₂CH₂OCH₂CH₂OR where R is an alkyl grouphaving 1 to 6 carbon atoms. Thus, in one variation, the ethylene glycolderivative is diethyleneglychol monoethyl ether. In one aspect, theketone is acetone. In another aspect, the polar aprotic solvent ispropylene carbonate. In another aspect, the alcohol is benzyl alcohol orethanol. In a particular variation, the composition comprises benzylalcohol and ethanol.

Kits are also provided herein, such as kits comprising any of thepreceding pharmaceutical compositions. In one aspect, the kit furthercomprises instructions for use in the treatment of onychomycosis, whichin one aspect is distal subungual onychomycosis.

Articles of manufacture are also provided, such as articles ofmanufacture comprising a container in which any of the precedingpharmaceutical compositions is contained. In one aspect, the containeris plastic. In another aspect, the container is a device. In aparticular variation, the article of manufacture comprises a unit dosageform of the composition.

In one aspect, a pharmaceutical composition of luliconazole is provided,wherein the composition comprises from about 5 weight percent to about15 weight percent luliconazole; from about 5 weight percent to about 25weight percent acetone; from about 1 weight percent to about 15 weightpercent propylene carbonate; from about 15 weight percent to about 35weight percent of an ethylene glycol derivative, which in certainembodiments is of the formula HOCH₂CH₂OCH₂CH₂OR where R is an alkylgroup having 1 to 6 carbon atoms (e.g., ethyl); and from 0.01 weightpercent to about 6 weight percent benzyl alcohol. In one aspect, thecomposition comprises about 2 weight percent to about 4 weight percentbenzyl alcohol. The composition may additionally contain a film formingagent, e.g., in from 0.01 weight percent to about 4 weight percent. Inone aspect, the film-forming agent is a maleic anhydride/methyl vinylether copolymer, such as Gantrez® ES-425 or Gantrez® ES-435. Thecomposition may also contain an alcohol, such as ethanol, which in onevariation is present in the composition in from about 35 weight percentto about 45 weight percent. It is understood that reference to relativeweight percentages assumes that the combined total weight percentages ofall components in the formulation add up to 100. It is furtherunderstood that relative weight percentages of one or more componentsmay be adjusted upwards or downwards such that the weight percent of thecomponents in the composition combine to a total of 100. For example,reference to a composition comprising from about 5 weight percent toabout 15 weight percent luliconazole; from about 5 weight percent toabout 25 weight percent acetone; from about 1 weight percent to about 15weight percent propylene carbonate; from about 15 weight percent toabout 35 weight percent of an ethylene glycol derivative, which incertain embodiments is of the formula HOCH₂CH₂OCH₂CH₂OR where R is analkyl group having 1 to 6 carbon atoms (e.g., ethyl); and from 0.01weight percent to about 6 weight percent benzyl alcohol intends acomposition wherein the weight percent of the composition components addto a total of 100 (e.g., where additional components account for anyamount under 100).

In one variation, compositions are provided wherein one or more of thecomponents (in some embodiments all of the components) of thecomposition are within 15%, or in an alternative embodiment, 10%, of theweight percent of each component as described in a product labelaccompanying distribution of the composition. For example, a compositionwhose accompanying product label at distribution lists 10 weight percentof luliconazole intends in one embodiment compositions comprising 9 to11 weight percent luliconazole. It is understood that the weight percentof one or more components of these formulations can change over time(e.g., upon storage, due to volatility of one more components, such asacetone).

In some embodiments, “about X” refers to within 15 percent of X for anyone (or in some embodiments all) components in a composition. In otherembodiments, “about X” refers to within 10 percent of X for any one (orin some embodiments all) components in a composition.

Other relative weight percentages of the composition components areenvisioned, e.g., a composition may comprise from about 9 weight percentto about 11 weight percent luliconazole; from about 8 weight percent toabout 15 weight percent acetone; from about 3 weight percent to about 8weight percent propylene carbonate; from about 20 weight percent toabout 30 weight percent of an ethylene glycol derivative, which incertain embodiments of the formula HOCH₂CH₂OCH₂CH₂OR where R is an alkylgroup having 1 to 6 carbon atoms; and benzyl alcohol in at least 0.01weight percent but no more than about 5 weight percent. Suchcompositions may also contain a film forming agent, such as a maleicanhydride/methyl vinyl ether copolymer, e.g., in from 0.01 weightpercent to about 4 weight percent. Such compositions may additionallycontain an alcohol, such as ethanol, e.g., in from about 35 weightpercent to about 45 weight percent.

Pharmaceutical compositions comprising about 5 weight percent to about15 weight percent luliconazole, benzyl alcohol, acetone and propylenecarbonate are also provided. Such compositions may additionally containethanol and/or an ethylene glycol derivative of the formulaHOCH₂CH₂OCH₂CH₂OR where R is an alkyl group having 1 to 6 carbon atoms,such as ethyl.

Pharmaceutical compositions comprising luliconazole, an ethylene glycolderivative of the formula HOCH₂CH₂OCH₂CH₂OR where R is an alkyl grouphaving 1 to 6 carbon atoms and at least two of benzyl alcohol, acetone,propylene carbonate and ethanol are also described herein. In oneaspect, such compositions comprise at least three of benzyl alcohol,acetone, propylene carbonate and ethanol. In a particular aspect, suchcompositions comprise benzyl alcohol, acetone and propylene carbonate,wherein the ethylene glycol derivative, acetone and propylene carbonatewhen taken together account for about 40 weight percent to about 45weight percent of the composition.

Also provided are pharmaceutical compositions comprising luliconazoleand at least four of benzyl alcohol, acetone, propylene carbonate,ethanol and an ethylene glycol derivative of the formulaHOCH₂CH₂OCH₂CH₂OR where R is an alkyl group having 1 to 6 carbon atoms(e.g., ethyl).

In one variation of the luliconazole formulations containing benzylalcohol, the composition comprises at least 0.01 weight percent but nomore than about 5 weight percent benzyl alcohol. In other aspects, theluliconazole formulations contain about 2 to about 4 weight percentbenzyl alcohol.

In particular variations, compositions of luliconazole comprise about 8weight percent to about 15 weight percent luliconazole. In furthervariations, compositions of luliconazole comprise about 10 weightpercent or about 12.5 weight percent luliconazole.

In luliconazole compositions comprising a film forming agent, in oneaspect the film forming agent is present in from 0.01 weight percent toabout 4 weight percent. In one aspect, the film-forming agent is amaleic anhydride/methyl vinyl ether copolymer, such as Gantrez® ES-425or Gantrez® ES-435.

In one aspect, luliconazole compositions described herein aresubstantially anhydrous.

The luliconazole compositions may provide a clear solution withoutevidence of crystal formation upon visual inspection after 6 months ofstorage at any of 5° C., 25° C. and 40° C. Such compositions solubilizeluliconazole under the given conditions.

The luliconazole compositions may provide a stable composition ofluliconazole in that the compositions contain at least about 95% of thetheoretical maximum amount of luliconazole after 6 months of storage atany of 5° C., 25° C. and 40° C. The amount of luliconazole in solutionmay be measured by methods known in the art, which may include themethods described herein.

The luliconazole compositions may both solubilize luliconazole andprovide a stable composition in that such compositions provide a clearsolution without evidence of crystal formation upon visual inspectionafter 6 months of storage at any of 5° C., 25° C. and 40° C. and whereinthe composition contains at least about 95% of the theoretical maximumamount of luliconazole after 6 months of storage at any of 5° C., 25° C.and 40° C.

The compositions may also exhibit efficacy against fungal infections,such as onychomycosis. In one aspect, the compositions provided hereineradicates at least 80% of a fungal infection of the nail after 14 daysof treatment, as measured by the recovery of less than 20% of thetheoretical amount of recoverable ATP from the fungus. Preferably, suchcompositions result in both high (e.g., greater than any of 80% or 85%or 90% or 95% or 98% or 99%) mycological cure and clinical cure rates.

The compositions described may also provide for penetration ofluliconazole through a nail after contacting the surface of the nail,such as a toenail, with a composition described herein. For example, inone aspect a luliconazole formulation comprising about 10 weight percentluliconazole provides at least about any of 50 or 75 or 100 or 120 or140 or 160 or 175 or 200 or more μg/cm² of luliconazole penetrationthrough a 0.5-0.8 mm thick or 0.5-1.2 mm nail when 1 μL the compositionis applied to a 0.05 cm² area of the nail once daily for 3 days. In onevariation, a luliconazole formulation comprising about 10 weight percentluliconazole provides at least any of 80 or 90 or 100 or 120 or 150 ormore μg/cm²/day of luliconazole penetration through a 0.5-0.8 mm or a0.5-1.2 mm thick nail when 1 μL the composition is applied to a 0.05 cm²area of the nail once daily for 3 days.

In one variation, the luliconazole composition is free of any of analpha-hydroxycarboxylic acid (such as lactic acid),N-methyl-2-pyrrolidone (NMP) and crotamiton. In one aspect, theluliconazole composition is free of all of an alpha-hydroxycarboxylicacid (such as lactic acid), NMP and crotamiton. In another variation,the composition is free from any one or more (and in a particularembodiment, all of) the following: triacetin; 2-ethyl-1,3-hexanediol;lauromacrogol; polyoxyethylene; polyoxypropylene; propylene glycol;lactic acid; polypropylene glycols, diesters of dibasic acids;triacetin; 2-ethyl-1,3-hexanediol; lauromacrogol;polyoxyethylene-polyoxypropylene glycols; glycono-d-lactone; propyleneglycol; glycerin; water (including free of 0.1-35% by mass of water);anionic surfactant; and a cellulose thickener.

Formulations having a quick drying time one applied to the nail are alsoprovided, such as formulations that dry in less than about any of 5 or 3or 2 minutes after application to a nail.

In another variation, the composition, when applied to a nail, leaves aminimal residue or film of luliconazole on the nail.

A method for treating or ameliorating a disease comprising the topicaladministration of a composition is provided herein. In one aspect, thedisease is dermatomycosis or an onychomycosis, such as onychomycosis ofa toenail and/or fingernail. In another aspect, the disease is Tineacorporis, Tinea cruris or Tinea pedis.

A method of treating onychomycosis in an individual in need thereof isprovided, which in one aspect may be a method of treating distalsubungual onychomycosis of a toenail and/or fingernail. In one aspect,the methods involve a once daily application of a luliconazolecomposition provided herein, such as a composition comprising about 10weight percent luliconazole, to the infected nail.

Methods of delivering luliconazole to the underside of a nail and/or thenail bed are provided, wherein the method comprises administering aluliconazole composition described herein to the surface of a nail. Inone aspect of the method, a luliconazole composition is applied to thesurface of the nail once daily for a period of time, such as any of 1 or2 or 3 or 4 or 5 or 6 or 9 or 12 months.

Methods of penetrating a nail, such as a fingernail or toenail, withluliconazole by contacting a nail surface with a luliconazoleformulation as described herein are also provided. In one aspect, themethods employ a luliconazole formulation comprising about 10 weightpercent luliconazole.

An individual that has or is suspected of having onychomycosis mayadminister a luliconazole composition according to the methods describedherein. In one aspect, the individual is a mammal, such as a human. In aparticular aspect, the individual is a human and the methods providedare directed to treating a human nail. In one aspect, the individual isdiabetic, is of an advanced age or is immunocompromised.

Methods of preparing a pharmaceutical composition of luliconazole arealso provided, such as methods comprising combining luliconazole with anethylene glycol derivative of the formula HOCH₂CH₂OCH₂CH₂OR where R isan alkyl group having 1 to 6 carbon atoms (e.g., ethanol), acetone,propylene carbonate, benzyl alcohol and ethanol. In one aspect, a methodof preparing a luliconazole composition comprises: (a) dissolvingluliconazole in one or both of benzyl alcohol and the ethylene glycolderivative; and (b) adding ethanol, propylene carbonate and acetone, toprovide the composition, where a maleic anhydride/methyl vinyl ethercopolymer may optionally be included in step (b) of the method.

Kits are also described, wherein the kits comprise a luliconazolecomposition as provided herein, and may further comprise instructionsfor use, such as in the treatment of onychomycosis, which may be distalsubungual onychomycosis.

Articles of manufacture comprising a container in which a luliconazolecomposition provided herein is contained are also provided. In oneaspect, the container is plastic. In one aspect, the container is glass.In another aspect, the container is a device, such as a devicecontaining a unit dosage form of the luliconazole composition.

Other aspects of the invention are provided throughout.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A and 1B are graphs of scoring results for the Erythema andEschar formation for days 1-28 in a dermal irritation study assessingthe effect of a 12.5 weight percent luliconazole formulation.

FIGS. 2A and 2B are graphs of scoring results for Edema Formation fordays 1-28 in a dermal irritation study assessing the effect of a 12.5weight percent luliconazole formulation.

FIGS. 3A, 3B, 3C and 3D are graphs of scoring results for the Erythemaand Eschar and Edema formation for days 35 and 42 in a dermal irritationstudy assessing the effect of a 12.5 weight percent luliconazoleformulation.

FIG. 4 is a linear regression of a 6 month stability study at 25° C. fora 10 weight percent luliconazole formulation through 2 years, indicatingthat the product will remain stable for up to 24 months.

FIG. 5 is a comparison of % ATP recovered after treatment with a 12.5weight percent luliconazole formulation as compared to infected controlfollowing 7, 14 and 21 days application, demonstrating that the 12.5weight percent luliconazole solution exerted potent fungicidal activityagainst dermatophytic hyphae after 7 days of once daily application andreduced the ATP content to non-infected baseline levels after 14 days ofapplication, whereas Penlac® showed only partial antifungal activitythroughout the experimental period.

FIG. 6 is a graph depicting the amount of luliconazole recovered fromdifferent nail depths after application of a 10 weight percentluliconazole formulation and placebo formulation (Mean±SEM (n=6)),indicating that the amount of luliconazole recovered from the nailsamples correlated with the depth of the nail assayed, whereby deeperlayers of the nail contained less luliconazole.

FIG. 7 is a graph depicting luliconazole's permeation through the nailafter continuous dosing for 7 and 21 days (Mean±SEM, n=6) with assaytime points for the 7 day dosing experiment at T=0, 3 and 7 days and forthe 21 day dosing experiment T=7, 14 and 21 days, showing steady statepermeation up to 7 days in the 7 day experiment and up to 14 days in the21 day experiment.

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutical compositions of luliconazole in a solvent system thatsolubilizes a sufficient amount of luliconazole for the treatment ofonychomycosis, is stable over time, and maintains the advantages of aneffective therapeutic for the treatment of onychomycosis (e.g., safety,high patient compliance, etc.) are provided. Methods of using and makingpharmaceutical compositions of luliconazole are also embraced, as arekits and articles of manufacture comprising the luliconazolecompositions.

It is understood that aspects and embodiments of the invention describedherein include “consisting” and/or “consisting essentially of” aspectsand embodiments.

Pharmaceutical Compositions

Although certain pharmaceutical compositions comprising up to 5 weightpercent luliconazole are known, pharmaceutical compositions comprisinggreater than 5 weight percent of luliconazole are desired for use in thetreatment of onychomycosis in view of the challenges associated witheffective treatment of this difficult to eradicate infection. Higherconcentrations of luliconazole in a pharmaceutical composition (e.g., acomposition comprising about 10 weight percent to about 15 weightpercent luliconazole) applied to a nail are much more likely to be ableto deliver a therapeutically effective amount of luliconazole to thesite of infection (e.g., a toenail, including the underside of the nail,and the nail bed) and result in complete and effective treatment that isless susceptible to reinfection and/or relapse. In addition, higherconcentration compositions of luliconazole may provide easier treatmentregimens, such as less than once-daily applications of the compositionto an infected nail. Compositions that are stable over time and under avariety of conditions are also provided.

The difficulties in achieving higher concentration luliconazolepharmaceutical compositions suitable for chronic use are multifold. Theyinclude safety considerations as well as the interrelated andinterdependent performance characteristics of a multi-solvent system,which impact the ability of the solvent system to dissolve a sufficientamount of luliconazole and its stability over time. In addition, patientcompliance associated with chronic application of the composition to aninfected nail is affected. That is, a solvent system containing higherluliconazole concentrations should adequately dissolve a sufficientamount of luliconazole, be safe for chronic use, provide a homogenousand physically stable composition with appropriate rheologicalproperties, be suitable for application to the nail, have a relativelyshort drying time upon application, produce little to no irritation whenapplied, deliver a therapeutically effective amount of luliconazole tothe site of infection (e.g., a toenail and/or nail bed), be chemicallystable with adequate antimicrobial properties and be convenient to theuser. A highly tuned system is thus required to adequately address eachof these formulation challenges. The pharmaceutical compositionsdescribed herein meet each of the formulation challenges and compriseluliconazole in concentrations sufficient for use in the treatment ofonychomycosis.

Luliconazole is practically insoluble in water and requires asubstantially non-aqueous solvent for its complete dissolution. Theluliconazole pharmaceutical compositions herein provide good efficacy inmodels of onychomycosis, are safe for chronic use and are stable overtime. Moreover, the compositions are generally formulated withingredients and at concentrations which are safe for topicalapplication, as described in the U.S. Food and Drug Administration'sInactive Ingredient Guide (IIG), and contain a concentration ofluliconazole sufficient for use in the treatment of onychomycosis.

Although Transcutol™ P is referred to in certain instances, it isunderstood that compositions comprising diethylene glycol monoethylether may be used. In addition, although Gantez (including Gantrez ES®435 and Gantrez ES® 425) is referred to in certain instances, it isunderstood that compositions comprising butyl ester of PVM/MA copolymermay be used (such as butyl ester of PVM/MA copolymer, 38-52% isopropylalcohol, <10% butyl alcohol). In addition, it is understood thatreference to Alcohol (200 Proof) includes and intends ethanol.

In one aspect, a pharmaceutical composition of luliconazole comprisingfrom about 9 weight percent to about 12.5 weight percent luliconazole orfrom about 10 weight percent to about 12.5 weight percent luliconazole;about 12 weight percent acetone; about 5 weight percent propylenecarbonate; about 25 weight percent HOCH₂CH₂OCH₂CH₂OR where R is an alkylgroup having 1 to 6 carbon atoms (e.g., ethyl) and benzyl alcohol in atleast a detectable amount but in no more than about 4 weight percent isprovided. In one variation, the composition also comprises from about 40weight percent to about 45 weight percent ethanol. The foregoingcompositions in one aspect also comprise a film forming agent, such asGantrez® ES-425 (which uses ethanol and butyl alcohol as a solvent) orGantrez® ES-435 (which uses an isopropanol-based solvent). In aparticular variation, a pharmaceutical composition of luliconazole isprovided, wherein the composition comprises between about 10 weightpercent luliconazole and about 15 weight percent luliconazole; about 12weight percent acetone; about 5 weight percent propylene carbonate;about 25 weight percent HOCH₂CH₂OCH₂CH₂OR where R is an alkyl grouphaving 1 to 6 carbon atoms (e.g., ethyl); benzyl alcohol in about 2weight percent to about 4 weight percent; and Gantrez® ES-435 in about 1weight percent.

In any formulation described herein in which the weight percent of thelisted components of the composition is less than 100, in one variation,the composition further comprises ethanol in a weight percent thatprovides a total weight percent of 100 for the composition. For example,in one aspect, a pharmaceutical composition of luliconazole is provided,wherein the composition comprises between about 10 weight percentluliconazole and about 15 weight percent luliconazole; about 12 weightpercent acetone; about 5 weight percent propylene carbonate; about 25weight percent HOCH₂CH₂OCH₂CH₂OR where R is an alkyl group having 1 to 6carbon atoms (e.g., ethyl); benzyl alcohol in about 2 weight percent toabout 4 weight percent; Gantrez® ES-435 in about 1 weight percent; andethanol in a weight percent that provides a total of 100 weight percentfor the composition. In a particular variation, a pharmaceuticalcomposition of luliconazole is provided, comprising about 40.5 weightpercent ethanol; about 4 weight percent benzyl alcohol; about 5 weightpercent propylene carbonate; about 12 weight percent acetone; about 25weight percent HOCH₂CH₂OCH₂CH₂OR where R is an alkyl group having 1 to 6carbon atoms (e.g., ethyl); and about 12.5 weight percent luliconazole.

Because pharmaceutical compositions of luliconazole for chronicapplication to the nail are provided, it is important that mixed solventcomponents that have higher safety concerns than others are minimized.For example, in one variation of the luliconazole pharmaceuticalcompositions provided herein, the compositions contain sufficiently highluliconazole concentrations (e.g., about 10 weight percent luliconazoleor more) for use in the treatment of onychomycosis and where thecompositions contain benzyl alcohol in detectable amounts but no morethan about 5 weight percent. Benzyl alcohol, which is a highly effectivesolvent for dissolving luliconazole, may thus be used sparingly in thepresent compositions. Use of less than about any of 6 or 5 or 4 or 3 or2 weight percent benzyl alcohol can limit an individual's exposure tobenzyl alcohol as compared to compositions containing greater amounts ofbenzyl alcohol, and result in a reduction or elimination of hemolyticeffects associated with its exposure. This may be especially importantin the context of chronic exposure of an individual to benzyl alcohol,e.g., by the daily use of a composition containing benzyl alcohol for aperiod of time that can last several months or a year or more.Significantly, mixed solvent systems comprising luliconazoleconcentrations in amounts sufficient to treat onychomycosis (e.g., about10 weight percent to about 15 weight percent) are able to adequatelysolubilize luliconazole using only relatively low amounts of benzylalcohol. Thus, stable pharmaceutical compositions for chronic use in thetreatment of onychomycosis comprising only about 4 weight percent benzylalcohol or less, are provided. In yet another variation, suchcompositions contain about 2 weight percent benzyl alcohol. Inparticular variations, such compositions further comprise at least oneof acetone, propylene carbonate and diethylene glycol monoethyl ether.In still another variation, such compositions further comprise any twoof acetone, diethylene glycol monoethyl ether and propylene carbonate.In still another variation, such compositions comprise acetone,diethylene glycol monoethyl ether and propylene carbonate.

In one variation, a pharmaceutical composition for the topical treatmentof onychomycosis is provided, wherein the composition comprisesluliconazole, diethylene glycol monoethyl ether, acetone and propylenecarbonate. In one such variation, diethylene glycol monoethyl ether,acetone and propylene carbonate together account for about 40 weightpercent to about 45 weight percent of the composition. In anothervariation, the multi-component solvent solution comprises acetone,propylene carbonate, diethylene glycol monoethyl ether and benzylalcohol. A pharmaceutical composition comprising luliconazole anddiethylene glycol monoethyl ether and at least two of benzyl alcohol,acetone, propylene carbonate and ethanol is also provided for use in thetreatment of onychomycosis. Also described is a pharmaceuticalcomposition comprising luliconazole and at least four of benzyl alcohol,acetone, propylene carbonate, ethanol and diethylene glycol monoethylether.

In one aspect, the pharmaceutical luliconazole compositions furthercomprises a film forming agent, such as Gantrez (e.g., Gantrez® ES-425or Gantrez® ES-435). The film forming agent may be present in one about1 weight percent. In one variation, the compositions provided hereincomprise Gantrez® ES-435 in about 1 weight percent.

The pharmaceutical compositions of luliconazole for chronic applicationto the nail contain sufficiently high luliconazole concentrations suchthat the composition is suitable for use in the treatment ofonychomycosis. In one aspect the pharmaceutical composition comprisesabout 8 weight percent luliconazole. In one aspect, the pharmaceuticalcomposition comprises about 10 weight percent luliconazole. In anotheraspect, the pharmaceutical composition comprises about 12.5 weightpercent luliconazole. In yet another aspect, the pharmaceuticalcomposition comprises between about 10 weight percent luliconazole andabout 15 weight percent luliconazole. In still a further aspect, thepharmaceutical composition comprises between about 10 weight percentluliconazole and about 12.5 weight percent luliconazole. In a furtheraspect, the pharmaceutical composition comprises between about 8 weightpercent luliconazole and about 12 weight percent luliconazole. In afurther aspect, the pharmaceutical composition comprises between about 9weight percent luliconazole and about 11 weight percent luliconazole.

In one aspect, the compositions described herein are substantiallyanhydrous. By substantially anhydrous it is meant that the compositioncontains no more than about 5 weight percent water. A substantiallyanhydrous composition may in one variation contain no more than about 3weight percent water. A composition containing no more than about 2weight percent water is also substantially anhydrous, as is acomposition containing no more than about 1 weight percent water or 0.5weight percent water. In one variation, a composition as describedherein does not contain detectable levels of water.

The compositions provided herein are, in one aspect, free of any one ormore of an alpha-hydroxycarboxylic acid (e.g., lactic acid), NMP andcrotamiton.

In one variation, a pharmaceutical composition of luliconazole is clear,indicating that luliconazole is soluble in the composition. In aparticular variation, a pharmaceutical composition of luliconazoleremains a clear solution, without evidence of crystal formation uponvisual inspection after any of 1 or 2 or 3 or 4 or 5 or 6 months ofstorage at any of 5° C., 25° C. and 40° C.

In one variation, a pharmaceutical composition of luliconazole ischemically stable, as evidenced by any more or more of the following:(i) the composition contains at least about any of 80% or 85% or 90% or95% of the theoretical maximum amount of luliconazole after 2 or 4 or 6or 12 or 18 or 24 or more months of storage at any of 5° C., 25° C. and40° C., where the theoretical maximum amount of luliconazole is theamount of luliconazole present in the composition at the time thecomposition is prepared, which may be referred to herein as time 0 (ii)the composition contains no more than any of 0.2 or 0.3 or 0.5 or 0.75or 1 weight percent of the Z form of luliconazole after any of 1 or 2 or3 or 4 or 5 or 6 or 12 or more months of storage at any of 5° C., 25° C.and 40° C.; (iii) the composition contains no more than any of 0.2 or0.3 or 0.5 or 0.75 or 1 or 2 or 3 or 4 or 5 weight percent of the SEform of luliconazole after any of 1 or 2 or 3 or 4 or 5 or 6 or 12 ormore months of storage at any of 5° C., 25° C. and 40° C.; (iv) thecomposition contains no more than any of 0.5, or 1 or 2 or 3 or 4 or 5combined weight percent of the Z and SE forms of luliconazole after anyof 1 or 2 or 3 or 4 or 5 or 6 or 12 or more months of storage at any of5° C., 25° C. and 40° C.; and (v) the composition contains at leastabout any of 80% or 90% or 100% or 110% label of luliconazole after anyof 1 or 2 or 3 or 4 or 5 or 6 or 12 or more months of storage at any of5° C., 25° C. and 40° C.

The pharmaceutical composition, when applied to an individual's nail, inone aspect leaves only a minimal residue or film of luliconazole on thenail.

The pharmaceutical compositions of luliconazole for chronic applicationto the nail in one aspect provide for the penetration of atherapeutically effective amount of luliconazole through a nail after 3days of continuous dosing of the composition to the surface of the nail.In one aspect, the composition comprises about 10 weight percent toabout 15 weight percent luliconazole, wherein the composition eradicatesat least 80% of a fungal infection of the nail after 14 days oftreatment, as measured by the recovery of less than 20% of thetheoretical amount of recoverable ATP from the fungus. In one aspect,the composition comprises about 10 weight percent to about 15 weightpercent luliconazole, wherein the composition, when applied to the nailonce daily for about any of 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or10 or 11 or 12 months, results in at least any of 80% or 85% or 90% or95% or 100% mycological cure and/or complete clinical cure, as evaluatedby methods known in the art, which in one variation are the methodsdescribed herein.

The compositions described may also provide for penetration ofluliconazole through a nail, such as a toenail, after a period of timefollowing application of the composition to the nail surface. Forexample, in one aspect a luliconazole formulation comprising about 10weight percent luliconazole provides at least about any of 50 or 75 or100 or 120 or 140 or 160 or 175 or 200 or more μg/cm² of luliconazolepenetration through a 0.5-0.8 mm thick or 0.5-1.2 mm thick nail when 1μL of the composition is applied to a 0.05 cm² area of the nail oncedaily for 3 days. In one variation, a luliconazole formulationcomprising about 10 weight percent luliconazole provides at least any of80 or 90 or 100 or 120 or 150 or more μg/cm²/day of luliconazolepenetration through a 0.5-0.8 mm thick or 0.5-1.2 mm thick nail when 1μL of the composition is applied to a 0.05 cm² area of the nail oncedaily for 3 days.

The pharmaceutical compositions described here may be in anypharmaceutically acceptable form, including but not limited to a liquid,gel, spray, foam and the like.

Methods of Use

The luliconazole pharmaceutical compositions described herein may beused in a method of treating onychomycosis in an individual in needthereof, comprising contacting the individual's nail with thecomposition. In one aspect, the individual is a mammal, such as a human.In a particular aspect, the individual is a human and the methodsprovided are directed to treating a human nail. Treatment of allcategories and combinations of categories of onychomycosis with theluliconazole pharmaceutical compositions are embraced. For example, inone aspect, a method of treating distal subungual onychomycosis isprovided, wherein the method comprises contacting the infected nail withthe luliconazole composition. In one aspect, the nail of the presentmethod is a toenail. In another variation, the nail of the presentmethod is a fingernail.

In a particular variation, methods of treating onychomycosis (includingbut not limited to distal subungual onychomycosis) of a toenail areprovided, comprising contacting the infected toenail with a luliconazolepharmaceutical composition.

A luliconazole pharmaceutical composition described herein above andthroughout may be used in the methods of treating onychomycosis, thesame as if each and every composition were specifically and individuallylisted for use in the treatment of onychomycosis. For example, it isunderstood that a method of treating onychomycosis, e.g., distalsubungual onychomycosis, with a composition of luliconazole comprisingfrom about 10 weight percent to about 12.5 weight percent luliconazole;about 12 weight percent acetone; about 5 weight percent propylenecarbonate; about 25 weight percent diethylene glycol monoethyl ether;and benzyl alcohol in at least a detectable amount but in no more thanabout 4 weight percent is provided.

Methods of penetrating a nail with luliconazole, comprising contactingthe individual's nail with a luliconazole pharmaceutical compositionprovided herein. In one aspect, the nail of the present method is atoenail. In another variation, the nail of the present method is afingernail. In one aspect, a method of penetrating a nail withluliconazole is provided by administering a composition comprising atleast about any of 8 or 10 or 12 weight percent luliconazole to theindividual's nail once daily for at least about any of 3 or 7 or 21days. In one aspect, a method of penetrating a nail with luliconazole isprovided by administering a composition comprising at least about any of8 or 10 or 12 weight percent luliconazole to the individual's nail oncedaily for at least about any of 1 or 2 or 3 or 4 or 6 or 8 or 10 or 12months.

Methods of delivering luliconazole to a nail bed are provided, whereinthe method comprises administering a luliconazole composition describedherein to the surface of a nail. In one aspect of the method, aluliconazole composition is applied to the surface of the nail oncedaily for a period of time, such as any of 3 or 7 or 14 days or any of 1or 2 or 3 or 4 or 5 or 6 or 9 or 12 months. In a particular variation,the luliconazole formulation comprises about 9-11 weight percentluliconazole.

In any of the methods provided herein, in one aspect the individual isdiabetic, is of an advanced age or is immunocompromised. In any methodsdescribed herein in one aspect the individual is an individual for whomLamisil® and/or Sporanox® are contraindicated or who would require areduction in other medications (e.g., agents metabolized by CYP450 2D6or CYP3A4) if they were to be administered Lamisil® and/or Sporanox®.

In one embodiment, the methods described herein can be used inconjunction with another anti-fungal therapy, such as a therapy foronychomycosis. Various exemplary therapies, such as oral anti-fungaltherapies are described herein. Generally, in conjunction with refers togiving therapies in the context of a single treatment regimen.

In one aspect, treatment of onychomycosis is measured by a reduction inor the absence of the fungal infection. In one variation, treatment isachieved by an amelioration of one or more symptoms of the infection(e.g., onychomycosis), as detailed herein. Preferably, the treatmentsprovide both a reduction or absence of fungal infection and the regrowthof clear, healthy nail.

In another aspect, the methods provide for both the treatment ofonychomycosis and protection against relapse or reinfection, wherein theindividual does not become reinfected with a nail fungus for at leastabout any of 1 or 2 or 3 months after terminating treatment of apreviously infected nail for onychomycosis using a luliconazolepharmaceutical composition described herein.

Dosing Regimens and Amounts

The luliconazole pharmaceutical compositions for use in the treatment ofonychomycosis are administered to the nail of an individual in an amountthat provides a therapeutically effective amount of luliconazole to theinfected site, which in one aspect includes the toenail and nail bed.

In one variation, a luliconazole pharmaceutical composition isadministered to an infected nail once daily for the duration of theinfection, which may be any of at least 1 or 2 or 4 or 6 or 9 or 12months or more. In some instances, an individual will continueadministration of a luliconazole pharmaceutical composition for a periodof time after eradication of the infection, as a prophylactic measure toguard against reinfection and/or relapse. It is also contemplated thatdosing regimens for the treatment of onychomycosis may be less than oncedaily, e.g., once every other day or thrice weekly or twice weekly oronce weekly or twice a month or once a month. The less than once dailydosing regimens are particularly contemplated with luliconazolepharmaceutical compositions comprising from about 10 weight percentluliconazole to about 15 weight percent luliconazole.

In one variation of the methods, a topical daily dose of 0.1 mL of apharmaceutical composition comprising about 8 to about 15 weight percentluliconazole is provided. In one aspect, a method of treatingonychomycosis is provided wherein a topical daily dose of 0.1 mL of apharmaceutical composition comprising about 10 weight percentluliconazole is applied to each infected nail.

Mixed dosing regimens are also provided. Given the long period of timefor complete cure of onychomycosis, it is contemplated that in oneaspect, an individual will administer a luliconazole pharmaceuticalcomposition as provided herein once daily for a first period of time,after which the individual will administer the luliconazolepharmaceutical composition in a less than daily regimen (e.g., in onceweekly intervals) for a second period of time. Further tapering of thedosing interval is contemplated and may be determined based on progressof the individual's treatment.

Methods of Making Pharmaceutical Compositions

Also embraced herein is a method for preparing a pharmaceuticalcomposition of luliconazole for topical application, comprisingcombining luliconazole with diethylene glycol monoethyl ether, acetone,propylene carbonate, benzyl alcohol and ethanol.

In one aspect, the method comprises (a) dissolving luliconazole in oneor both of benzyl alcohol and diethylene glycol monoethyl ether; and (b)adding ethanol, propylene carbonate, acetone and Gantrez, to provide thecomposition.

In one variation, a formulation comprising a film former (e.g., Gantrez®ES-435 or Gantrez® ES-425), ethanol, benzyl alcohol, propylene carbonateand diethylene glycol monoethyl ether is prepared by mixing in a primarymixing vessel, the film former, ethanol, benzyl alcohol, propylenecarbonate and diethylene glycol monoethyl ether. Acetone andluliconazole are added and the contents are mixed until all solids arevisually dissolved. In one aspect, acetone and luliconazole are addedunder amber lighting.

In one embodiment, the invention embraces products produced from theprocesses described herein.

Kits

Kits comprising a luliconazole pharmaceutical composition are alsoprovided. In one aspect, the kit comprises instructions for use in thetreatment of onychomycosis. In a particular variation, the instructionsare directed to use of a luliconazole pharmaceutical composition for thetreatment of distal subungual onychomycosis.

Any luliconazole pharmaceutical composition detailed herein above andthroughout may be used in the kits, the same as if each and everycomposition were specifically and individually listed for use a kit. Forexample, it is understood that a kit comprising a luliconazolepharmaceutical composition comprising from about 10 weight percent toabout 12.5 weight percent luliconazole; about 12 weight percent acetone;about 5 weight percent propylene carbonate; about 25 weight percentdiethylene glycol monoethyl ether; and benzyl alcohol in at least adetectable amount but in no more than about 4 weight percent isprovided. The kit may optionally include instructions, such as for theuse in treating a nail (e.g., a toenail) for onychomycosis. The kit mayinclude additional components relating to care of a nail, such as a nailfile.

Articles of Manufacture

Articles of manufacture comprising a container in which a luliconazolepharmaceutical composition is contained are provided. The article ofmanufacture may be a bottle, vial, ampoule, single-use disposableapplicator, or the like, containing a luliconazole pharmaceuticalcomposition as described herein. The container may be formed from avariety of materials, such as glass or plastic and in one aspect alsocontains a label on, or associated with, the container which indicatesdirections for use in the treatment of onychomycosis.

In one aspect, the container is a medical device containing a unitdosage form of a luliconazole pharmaceutical composition. The device maybe a brush or applicator for applying the composition to the surface ofthe nail plate.

Unit dosage forms of the luliconazole pharmaceutical compositions arealso provided.

Any luliconazole pharmaceutical composition described herein above andthroughout may be used in the articles of manufacture, the same as ifeach and every composition were specifically and individually listed foruse an article of manufacture. For example, it is understood that aarticle of manufacture may comprise a luliconazole pharmaceuticalcomposition comprising from about 10 weight percent to about 12.5 weightpercent luliconazole; about 12 weight percent acetone; about 5 weightpercent propylene carbonate; about 25 weight percent diethylene glycolmonoethyl ether; and benzyl alcohol in at least a detectable amount butin no more than about 4 weight percent is provided.

DEFINITIONS AND FURTHER EMBODIMENTS

Unless specifically noted otherwise herein, the definitions of the termsused are standard definitions used in the art of organic synthesis andpharmaceutical sciences. Exemplary embodiments, aspects and variationsare illustrated in the figures and drawings, and it is intended that theembodiments, aspects and variations, and the figures and drawingsdisclosed herein are to be considered illustrative and not limiting.

As is well understood by one skilled in the art, reference to “about” avalue or parameter herein includes (and describes) embodiments that aredirected to that value or parameter per se. For example, “about X”includes description of and describes “X.”

“Therapeutically effective amount” means a drug amount that elicits anyof the biological effects listed in the specification.

“Treatment” includes any one or more of desirable endpoints, includingclinical endpoints, as described herein.

The term “composition” used herein may be used interchangeably with theterm “formulation.”

The compositions described herein are used to treat conditions of theskin or the nail. Examples of such conditions include, but are notlimited to, infections, inflammation, psoriasis, paronychia, benign ormalignant skin or nail tumors and aesthetic conditions. In one aspect ofthe present application, the compositions are used to treatdermatomycoses or onychomycosis.

Dermatomycoses refers to an infection of the skin caused bydermatophytes or other fungi. Examples of dermatomycoses include, butare not limited to Tinea corporis, Tinea cruris or Tinea pedis. Examplesof pathogens which are known to cause dermatomycoses include, but arenot limited to Trichophyton rubrum, Trichophyton interdigitale,Trichophyton rubrum (most common in New Zealand), Trichophytoninterdigitale, Trichophyton tonsurans (very common in the USA),Microsporum audouinii, Trichophyton violaceum, Microsporum ferrugineum,Trichophyton schoenleinii, Trichophyton megninii, Trichophytonsoudanense, Trichophyton yaoundei, Trichophyton mentagrophytes andTrichophyton tonsurans.

Onychomycosis refers to a fungal infection of the nail plate and/or nailbed, also known as Tinea unguium. Examples of pathogens which are knownto cause onychomycosis include, but are not limited to dermatophytes,such as Trichophyton rubrum, Trichophyton interdigitale, Epidermophytonfloccosum, Trichophyton violaceum, Microsporum gypseum, Trichophytontonsurans, Trichophyton soudanense and Trichophyton verrucosum; Candida,such as, Candida albicans and non-dermatophytic moulds, such asScopulariopsis brevicaulis and Fusarium species.

Onychomycosis can affect the nail plate, the nail bed (the tissuedirectly under the nail plate), the nail matrix or nail root (thethickened skin at the base of the nail from which the nail platedevelops), the cuticle, the hyponychium (the thickened layer ofepidermis beneath the free end of the nail), and the proximal andlateral nail folds (the skin adjacent to the base and sides of thenail). Onychomycosis can be categorized into several varieties based onclinical appearance. All categories of onychomycosis are encompassed inthe methods described herein, including distal and lateral subungualonychomycosis (DLSO), endonyx onychomycosis (EO), white superficialonychomycosis (WSO), proximal subungual onychomycosis (PSO), Candidaonychomycosis (CO) and total dystrophic onychomycosis (TDO). Anindividual with onychomycosis may have one variety or any combination ofvarieties.

Examples of active agents that may be employed in the formulationsdescribed herein include, but are not limited to, antibiotics,antifungals, anti-inflammatories, antipsoratic, anticancers, and otheractive agents steroids, methotrexate, cyclosporine, retinoids,pharmaceutically acceptable salts thereof and combinations thereof.

Examples of antifugal agents include, but are not limited to,ketoconazole, miconazole, bifonazole, butoconazole, clomidazole,clotrimazole, croconazole, eberconazole, econazole, fenticonazole,flutimazole, isoconazole, ketoconazole, lanoconazole, luliconazole,neticonazole, omoconazole, oxiconazole, setraconazole, sulconazole,tioconazole, fluconazole, itraconazole, terconazole, terbinafine,natrifine, amorolfine, amphotericin B, nystatin, natamaycin,flucytosine, griseofulvin, potassium iodide, butenafine, ciclopirox,ciloquinol (iodochlorhydroxyquin), haloprogin, tolnaftate, aluminumchloride, undecylenic acid, potassium permanganate, selenium sulphide,salicylic acid, zinc pyruthione, bromochlorsalicylanilide,methylrosaniline, tribromometacresol, undecylenic acid, polynoxylin,2-(4-chlorphenoxy)-ethanol, chlorophensesin, ticlatone, sulbentine,ethyl hydroxybenzoate, dimazole, tolciclate, sulphacetamide, benzoicacid and pharmaceutically acceptable salts thereof. A preferredantifungal agent is luliconazole, which is also described in Table 1b.

TABLE 1b Luliconazole Names and Description Name: luliconazoleDescription CAS Registry Number 187164-19-8 Chemical Names(−)-(E)-[(4R)-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene](1H-imidazol-1- yl)acetonitrile Chemical ClassImidazole Molecular Formula C₁₄H₉Cl₂N₃S₂ Company codes NND-502, PR-2699

Luliconazole has excellent antifungal activity against dermatophyte(Trichophyton, Microsporum, and Epidermaophyton spp.), Candida andMalassezia. Luliconazole also has excellent antifungal activity againstT. ruburm, which is the major dermatophyte in onychomycosis. Minimalinhibitory concentrations (MICs) of luliconazole against fresh clinicalisolates of the dermatopyte have been found to be between 0.00012 and0.004 μg/mL, and its fungicidal activity has been demonstrated in lowconcentrations. Luliconazole exhibits strong antifungal activity againstother pathogenic fungi (yeast-like fungus), Aspergillus, anddematiaceae). See, e.g., Niwano, Y, et al., In Vitro and In VivoAntidermatophyte Activities of NND-502, a Novel Optically ActiveImidazole Antimycotic Agent. Antimicrob. Agents Chemother. 1998;42:967-970 and Koga H. et al, In Vitro Antifungal Activities ofLuliconazole, a New Topical Imidazole. Med. Mycology, 2008:1-8.

In addition to having a broad antifungal spectrum, luliconazole has highretention in the skin and reversible binding to keratine. In animalinfection models, luliconazole has equivalent or stronger therapeuticeffects compared to commercially available externally appliedanti-fungal drugs within shorter application periods.

The phrase “luliconazole type” refers to any antifungal agents havingsimilar properties and activities against dermatophytes or other fungiknown or suspected to cause disease as luliconazole.

The term “stable” refers to a composition or a formulation that remainssubstantially unchanged or substantially unaltered under conditions ofmanufacture and storage over a period of time under specific conditions.In particular, the composition remains substantially unchanged orunaltered when kept at a temperature of about 30° C. or less, at about25° C. or less, at about 15° C. or less, at about 5° C. or less, for atleast one week, at least two weeks, at least three weeks or at leastfour weeks. In certain formulations of the antifungal agents as known inthe art, under certain conditions over a period of time, the agents mayprecipitate out or crystallize out from the formulation upon storage,and such precipitation or crystallization may be deemed to result in an“unstable” formulation.

The term “excipient” refers to an inactive substance used as a carrierfor the active agent for the compositions described herein. In oneaspect of the invention, excipients include by example an alcohol, suchas, but not limited to, ethanol or benzyl alcohol; a ketone, such as,but not limited to acetone; an ethylene glycol derivative, such as, butnot limited to diethylene glycol monoethyl ether (such as Transcutol™P), including the ethyl ether or methyl ether analogues; or polaraprotic solvents, such as, but not limited to dimethyl sulfoxide (DMSO)and propylene carbonate (PC). In other aspects of the invention,excipients include, without limitation, alpha-hydroxycarboxylic acidsand their salts and diesters of dibasic acids. In yet another aspect ofthe invention, the excipient is a surface active agent. Also includedherein are diisopropyl adipate, N-methyl-2-pyrrolidone and lactic acid.Examples of excipients include, but are not limited to1,2,6-hexanetriol, 1,3-dimethylol-5,5-dimethyl-hydantoin,1-o-tolylbiguanide, 2-amino-2-methyl-1-propanol, 2-ethylhexylsalicylate, acetic acid, acetone, acrylates copolymer, acrylic acidhomopolymer, acrylic acid/isooctylacrylate copolymer, adcote 72A103,adhesive tape, adhesive tape, aerotex resin 3730, ethyl alcohol,dehydrated ethyl alcohol, denatured ethyl alcohol, diluted 50% aqueousethyl alcohol, alkyl ammonium sulfonic acid betaine, alkyl aryl sodiumsulfonate, allantoin, almond oil, alpha-terpineol, alpha-tocopherol,aluminum acetate, aluminum chlorhydroxy allantoinate, aluminumhydroxide, aluminum hydroxide—sucrose, hydrated aluminum hydroxide gel,aluminum hydroxide gel F 500, aluminum hydroxide gel F 5000, aluminummonostearate, aluminum oxide, aluminum polyester, aluminum silicate,aluminum starch octenylsuccinate, aluminum stearate, aluminum sulfateanhydrous, amerchol C, amerchol-cab, ammonia solution, strong ammoniasolution, ammonium hydroxide, ammonium lauryl sulfate, ammoniumnonoxynol 4 sulfate, ammonium salt of C-12-C-15 linear primary alcoholethoxylate, ammonyx, amphoteric-2, amphoteric-9, anhydrous dibasiccalcium phosphate, anoxid SBN, antifoam, apricot kernel oil PEG-6esters, aquaphor, arlacel, arlatone 289, ascorbic acid, ascorbylpalmitate, canada balsam, beeswax, synthetic beeswax, beheneth-10,bentonite, bentonite, benzalkonium chloride, benzoic acid, benzylalcohol, betadex, boric acid, butyl alcohol, butyl ester of PVM/MAcopolymer, butyl stearate, butylated hydroxyanisole, butylatedhydroxytoluene, butylene glycol, butylparaben, C20-40 pareth-24, calciumacetate, calcium chloride, calcium hydroxide, caprylic/caprictriglyceride, caprylic/capric/stearic triglyceride, captan, caramel,carbomer 1342, carbomer 934, carbomer 934-p, carbomer 940, carbomer 941,carbomer 974P, carbomer 980, carbomer 980, carbomer 981, carbomerhomopolymer type C, carboxy vinyl copolymer, carboxymethylcellulose,carboxymethylcellulose sodium, carrageenan, carrageenan salt, castoroil, castor oil hydrogenated, cedar leaf oil, cellulose, cerasynt-se,ceresin, ceteareth-12, ceteareth-15, ceteareth-30, cetearyl alcohol,cetearyl alcohol/ceteareth-20, cetearyl octanoate, ceteth-10, ceteth-2,ceteth-20, ceteth-23, cetrimonium chloride, cetyl alcohol, cetyl esters,cetyl palmitate, cetylpyridinium chloride, chemoderm 6401B,chlorobutanol, chlorocresol, chloroxylenol, cholesterol, choleth-24,citric acid, citric acid monohydrate, hydrous citric acid, cocamidediethanolamine, cocamide ether sulfate, cocamine oxide, coco betaine,cocoa butter, cocoglycerides, cocomonoethanolamide, coconut oil,fractioned coconut oil, cocoyl caprylocaprate, collagen, coloringsuspension, cream base, creatinine, crospovidone, crospovidone,cyclomethicone, cyclomethicone/dimethicone copolyol, daubert 1-5 PESTR(matte) 164Z, dehydroacetic acid, dehymuls E, denatonium benzoate,dextrin, diazolidinylurea, dichlorobenzyl alcohol,dichlorodifluoromethane, dichlorotetrafluoroethane, diethanolamine,diethyl sebacate, diethylene glycol monoethyl ether, diethylene glycolmonoethyl ether, dihydroxyaluminum aminoacetate, diisopropanolamine,diisopropyl adipate, diisopropyl dimerate, dimethicone 350, dimethicone360, dimethicone copolyol, dimethicone MDX4-4210, dimethyl isosorbide,dimethyl sulfoxide, dioctyl phthalate, dipropylene glycol, disodiumcocoamphodiacetate, disodium laureth sulfosuccinate, disodium laurylsulfosuccinate, docosanol, docusate sodium, duro-TAK 280-2516, duro-TAK80-1196, duro-TAK 87-2070, duro-TAK 87-2194, duro-TAK 87-2287, duro-TAK87-2296, duro-TAK 87-2888, duro-TAK 87-2979, edetate sodium, edeticacid, entsulfon, entsulfon sodium, essence, bouquet 9200, ethyl acetate,ethyl hexanediol, ethyl oleate, ethylcellulose, ethylene glycol,ethylene vinyl acetate copolymer, ethylenediamine, ethylenediaminedihydrochloride, ethylene-propylene copolymer, ethylparaben, eudragit E100, fatty acid esters, fatty acid pentaerythriol ester, fatty acids,fatty alcohol citrate, ferric oxide, flavor rhodia pharmaceutical #RF451, formaldehyde, formaldehyde solution, gelatin, gelva 737,gluconolactone, glycerin, glyceryl citrate, glyceryl isostearate,glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryloleate, glyceryl oleate/propylene glycol, glyceryl palmitate, glycerylricinoleate, glyceryl stearate-laureth-23, glyceryl stearate SE,glyceryl stearate/PEG-100 stearate, glyceryl stearate-stearamidoethyldiethylamine, glycol distearate, guar gum, hair conditioner (18N195-1M),herbacol, hexylene glycol, hyaluronate sodium, plasticized hydrocarbongel, hydrochloric acid, diluted hydrochloric acid, hydrogen peroxide,hydrogenated palm/palm kernel oil PEG-6 esters, hydroxyethyl cellulose,hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctacosanylhydroxystearate, hydroxypropyl cellulose, hydroxypropyl cellulose,hypromellose, imidurea, ink flexographic pink, ink/polyethylene,terephthalate/aluminum/polyethylene/sodium polymethacrylate/ethylenevinylacetate copolymer, irish moss extract, isoceteth-20,isooctylacrylate, isopropyl alcohol, isopropyl isostearate, isopropylmyristate, isopropyl myristate, isopropyl myristate—myristyl alcohol,isopropyl palmitate, isopropyl stearate, isostearic acid, isostearylalcohol, jelene, kaolin, kathon CG, kathon CG II, lactate, lactic acid,dl-lactic acid, lactose, laneth, lanolin, lanolin alcohol-mineral oil,lanolin alcohols, acetylated lanolin alcohols, lanolin anhydrous,lanolin cholesterols, lanolin, hydrogenated, lauramine oxide,laurdimonium hydrolyzed animal collagen, laureth sulfate, laureth-2,laureth-23, laureth-4, lauric diethanolamide, lauric myristicdiethanolamide, lauryl lactate, lauryl sulfate, lecithin, lemon oil,light mineral oil, limonene, dl-, lipocol SC-15, magnesium aluminumsilicate, magnesium aluminum silicate hydrate, magnesium nitrate,magnesium stearate, mannitol, maprofix, medical adhesive modified S-15,medical antiform a-f emulsion, menthol, methoxypolyoxyethylene glycol350, methyl alcohol, methyl gluceth-10, methyl gluceth-120 dioleate,methyl gluceth-20, methyl gluceth-20 sesquistearate, methyl glucosesesquistearate, methyl laurate, methyl salicylate, methyl stearate,methylcellulose, methylchloroisothiazolinone, ethylisothiazolinone,methylparaben, microcrystalline wax, mineral oil, multisterol extract,myristyl alcohol, myristyl lactate, n,n-bis(2-hydroxyethyl)stearamide,n,n-dimethyl lauramine oxide, n-3-chloroallyl-methenamine chloride,n-decyl-methyl sulfoxide, niacinamide, nitric acid, nonoxynol-15,nonoxynol-9, octadecene-1/maleic acid copolymer, octoxynol-1,octoxynol-9, octyl hydroxystearate, octyldodecanol, octyldodecanol,oleic acid, oleth-10/oleth-5, oleth-2, oleth-20, oleyl alcohol, oleyloleate, olive oil, orvus k liquid, palmitamine oxide, parabens,paraffin, white soft paraffin, parfum creme 45/3, peanut oil, pectin,PEG 6-32 stearate/glycol stearate, PEG-22 methyl ether/dodecyl glycolcopolymer, PEG-25 propylene glycol stearate, PEG-45/dodecyl glycolcopolymer, peglicol-5-oleate, pegoxol 7 stearate, pentadecalactone,pentaerythritol cocoate, peppermint oil, perfume 25677, perfume bouquet,perfume E-1991, perfume GD 5604, perfume tana 90/42 SCBA, perfumeW-1952-1, petrolatum, white petrolatum, petroleum distillates, phenonip,phenoxyethanol, phenylmercuric acetate, phosphoric acid, pine needleoil, plastibase-50w, polacrilin, poloxamer 124, poloxamer 181, poloxamer182, poloxamer 188, poloxamer 237, poloxamer 407, polybutene,polycarbophil, polyester, fluoro-polyester chemical releasing agent,polyester fluorocarbon diacrylate, polyester polyamine copolymer,polyethylene, polyethylene glycol 1000, polyethylene glycol 1500,polyethylene glycol 1540, polyethylene glycol 200, polyethylene glycol300, polyethylene glycol 300-1600, polyethylene glycol 3350,polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol540, polyethylene glycol 600, polyethylene glycol 6000, polyethyleneglycol 8000, polyethylene glycol 900, polyethylene terephthalates,polyhydroxyethyl methacrylate, polyisobutylene, polyisobutylene1,200,000, polyisobutylene 1,200,000, polyisobutylene 35,000,polyisobutylene low molecular weight, polyisobutylene medium molecularweight, polyisobutylene/polybutene adhesive,polyoxyethylene-polyoxypropylene 1800, polyoxyethylene alcohols,polyoxyethylene fatty acid esters, polyoxyethylene propylene, polyoxyl100 glyceryl stearate, polyoxyl 100 stearate, polyoxyl 15 cocamine,polyoxyl 150 distearate, polyoxyl 2 stearate, polyoxyl 20 cetostearylether, polyoxyl 4 dilaurate, polyoxyl 40 hydrogenated castor oil,polyoxyl 40 stearate, polyoxyl 400 stearate, polyoxyl 50 stearate,polyoxyl 6 and polyoxyl 32 palmitostearate, polyoxyl 6 isostearate,polyoxyl 60 hydrogenated castor oil, polyoxyl 75 lanolin, polyoxyl 8laurate, polyoxyl 8 stearate, polyoxyl distearate, polyoxyl glycerylstearate, polyoxyl lanolin, polyoxyl stearate, polypropylene,polyquaternium-1, polyquaternium-10, polyquaternium-7, polysorbate 20,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65,polysorbate 80, polyvinyl acetate, polyvinyl alcohol, polyvinyl alcohol,polyvinyl chloride-polyvinyl acetate copolymer, polyvinylpyridine,potash, potassium citrate, potassium hydroxide, potassium soap,potassium sorbate, povidone acrylate copolymer, povidone hydrogel,povidone K29-32, povidone K90, povidone/eicosene copolymer, PPG-12/SMDIcopolymer, PPG-15 stearyl ether, PPG-20 methyl glucose ether distearate,PPG-26 oleate, product WAT, promalgen type G, promulgen D, promulgen G,propellant A-46, propyl gallate, propylene carbonate, propylene glycol,propylene glycol, propylene glycol, propylene glycol diacetate,propylene glycol dicaprylate, propylene glycol monolaurate, propyleneglycol monostearate, propylene glycol palmitostearate, propylene glycolricinoleate, propylene glycol/diazolidinylurea/methylparaben/propylparben, propylparaben, protein hydrolysate,quaternium-15, quaternium-52, quatrimycin hydrochloride, RA-2397,RA-3011, saccharin, saccharin sodium, safflower oil, scotchpak 1109,scotchpak 9739 backing film PET/EVA, SD alcohol 3A, SD alcohol 40, SDalcohol 40-2, SD alcohol 40b, silicon dioxide, colloidal silicondioxide, silicone, silicone adhesive 4102, silicone emulsion,silicone/polyester film strip, simethicone, simethicone emulsion, sipon1-20, sodium acetate, sodium acetate anhydrous, sodium alkyl sulfate,sodium benzoate, sodium cetearyl sulfate, sodium chloride, sodiumchloride, sodium citrate, sodium citrate, sodium cocoyl sarcosinate,sodium dodecyl benzene sulfonate, sodium formaldehyde sulfoxylate,sodium hydroxide, sodium iodide, sodium lactate, sodium laureth sulfate,sodium laureth-2 sulfate, sodium laureth-5 sulfate, sodium lauroylsarcosinate, sodium lauryl sulfate, sodium lauryl sulfoacetate, sodiummetabisulfite, sodium phosphate, dibasic sodium phosphate, dibasicanhydrous sodium phosphate, dibasic dihydrate sodium phosphate, sodiumphosphate, dibasic, heptahydrate monobasic sodium phosphate, monobasicsodium phosphate anhydrous, monohydrate sodium phosphate, monobasic,sodium polyacrylate, sodium pyrrolidone carboxylate, sodium sulfite,sodium sulfosuccinated undecyclenic monoalkylolamide, sodiumthiosulfate, sodium xylenesulfonate, solulan, somay 44, sorbic acidsorbitan, sorbitan monolaurate, sorbitan monooleate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitansesquioleate, sorbitol, sorbitol solution, soybean flour, soybean oil,spearmint oil, spermaceti, squalane, starch, starch aluminum octenylsuccinate, stearalkonium chloride, stearalkonium hectorite/propylenecarbonate, stearamidoethyl diethylamine, steareth-10, steareth-100,steareth-2, steareth-20, steareth-21, stearic acid,stearoxytrimethylsilane, steartrimonium hydrolyzed animal collagen,stearyl alcohol, stearyl citrate, styrene/isoprene/styrene blockcopolymer, sucrose, sucrose distearate, sucrose polyesters,sulfacetamide sodium, sulfuric acid, surfactol SQ, talc, tall oil,tallow glycerides, tartaric acid, tenox, tenox-2, tert-butyl alcohol,thimerosal, titanium dioxide, titanium dioxide, tocopherol,tocophersolan, triacetin, trichloromonofluoromethane, trideceth-10,medium chain triglycerides, trihydroxystearin, trilaneth-4 phosphate,trilaureth-4 phosphate, trisodium citrate dihydrate, trisodium citrate,anhydrous, trisodium hedta, triton X-200 sodium salt of alkylaurylpolyether sulfonate, trolamine, trolamine lauryl sulfate, tromethamine,tromethamine, tyloxapol, undecylenic acid, union 76 AMSCO-RES 6038,vegetable oil, hydrogenated vegetable oil, viscarin, viscose/cotton,wax, dehydag, emulsifying wax, white wax, wecobee FS, xanthan gum,xanthan gum and zinc acetate.

The term “surface active agents” includes a variety of ethylene glycolderivatives and other compounds including, withour limitation compoundsbelonging to the following classes: polyethoxylated fatty acids,PEG-fatty acid diesters, PEG-fatty acid mono-ester and all-estermixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oiltransesterification products, polyglycerized fatty acids, propyleneglycol fatty acid esters, mixtures of propylene glycol esters andglycerol esters, mono- and diglycerides, sterol and sterol derivatives,polyethylene glycol sorbitan fatty acid esters, polyethylene glycolalkyl ethers, sugar esters, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acidesters, lower alcohol fatty acid esters, and ionic surfactants. Certainof these have been disclosed as ethylene glycol derivatives before.Certain non-limiting, commercially available, examples for each class ofexcipient are provided below.

Polyethoxylated fatty acids can be used as excipients for thecompositions provided herein. Examples of commercially availablepolyethoxylated fatty acid monoester surfactants include: PEG 4-100monolaurate (Crodet L series, Croda), PEG 4-100 monooleate (Crodet 0series, Croda), PEG 4-100 monostearate (Crodet S series, Croda, and MyrjSeries, Atlas/ICI), PEG 400 distearate (Cithrol 4DS series, Croda), PEG100, 200, or 300 monolaurate (Cithrol ML series, Croda), PEG 100, 200,or 300 monooleate (Cithrol MO series, Croda), PEG 400 dioleate (Cithrol4D0 series, Croda), PEG 400-1000 monostearate (Cithrol MS series,Croda), PEG-1 stearate (Nikkol MYS-1EX, Nikko, and Coster K1, Condea),PEG-2 stearate (Niklol MYS-2, Nikko), PEG-2 oleate (Nikkol MYO-2,Nikko), PEG-4 laurate (Mapeg( ) 200 mL, PPG), PEG-4 oleate (Mapeg( ) 200MO, PPG), PEG-4 stearate (Kessco PEG 200 MS, Stepan), PEG-5 stearate(Nikkol TMGS-5, Nikko), PEG-5 oleate (Nikkol TMGO-5, Nikko), PEG-6oleate (Argon OL 60, Auschem SpA), PEG-7 oleate (Argon OL 70, AuschemSpA), PEG-6 laurate (Kessco PEG300 mL, Stepan), PEG-7 laurate (Lauridac7, Condea), PEG-6 stearate (Kessco, PEG300 MS, Stepan), PEG-8 laurate(Mapeg( ) 400 mL, PPG), PEG-8 oleate (Mapeg 400 MO, PPG), PEG-8 stearate(Mapeg) 400 MS, PPG), PEG-9 oleate (Emulgante A9, Condea), PEG-9stearate (Cremophor S9, BASF), PEG-10 laurate (Nikkol MYL-10, Nikko),PEG-10 oleate (Nikkol MYO-10, Nikko), PEG-12 stearate (Nikkol MYS-10,Nikko), PEG-12 laurate (Kessco PEG 600 mL, Stepan), PEG-12 oleate(Kessco PEG 600 MO, Stepan), PEG-12 ricinoleate (CAS 9004-97-1), PEG-12stearate (Mapeg 600 MS, PPG), PEG-15 stearate (Nikkol TMGS-15, Nikko),PEG-15 oleate (Nikkol TMGO-15, Nikko), PEG-20 laurate (Kessco PEG 1000mL, Stepan), PEG-20 oleate (Kessco PEG 1000 MO, Stepan), PEG-20 stearate(Mapeg 1000 MS, PPG), PEG-25 stearate (Nikkol MYS-25, Nikko), PEG-32laurate (Kessco@D PEG 1540 mL, Stepan), PEG-32 oleate (Kessco) PEG 1540MO, Stepan), PEG-32 stearate (Kessco PEG 1540 MS, Stepan), PEG-30stearate (Myrj 51), PEG-40 laurate (Crodet L40, Croda), PEG-40 oleate(Crodet 040, Croda), PEG-40 stearate (Emerest 2715, Henkel), PEG-45stearate (Nikkol MYS-45, Nikko), PEG-50 stearate (Myrj 53), PEG-55stearate (Nikkol MYS 55, Nikko), PEG-100 oleate (Crodet 0-100, Croda),PEG-100 stearate (Ariacel 165, ICI), PEG-200 oleate (Albunol 200 MO,Taiwan Surf.), PEG-400 oleate (LACTOMUL, Henkel), and PEG-600 oleate(Albunol 600 MO, Taiwan Surf.). Compositions of the application caninclude one or more of the polyethoxylated fatty acids above.

Polyethylene glycol fatty acid diesters can also be used as excipientsfor the compositions provided herein. Examples of commercially availablepolyethylene glycol fatty acid diesters include: PEG-4 dilaurate (Mapeg)200 DL, PPG), PEG-4 dioleate (Mapeg 200 DO, PPG), PEG-4 distearate(Kessco 200 DS, Stepan), PEG-6 dilaurate (Kessco PEG 300 DL, Stepan),PEG-6 dioleate (Kessco PEG 300 DO, Stepan), PEG-6 distearate (Kessco PEG300 DS, Stepan), PEG-8 dilaurate (Mapeg 400 DL, PPG), PEG-8 dioleate (Mapeg 400 DO, PPG), PEG-8 distearate (Ma peg 400 DS, PPG), PEG-10dipalmitate (Polyaldo 2PKFG), PEG-12 dilaurate (Kessco PEG 600 DL,Stepan), PEG-12 distearate (Kessco PEG 600 DS, Stepan), PEG-12 dioleate(Mapeg) 600 DO, PPG), PEG-20 dilaurate (Kessco PEG 1000 DL, Stepan),PEG-20 dioleate (Kessco) PEG 1000 DO, Stepan), PEG-20 distearate (KesscoPEG 1000 DS, Stepan), PEG-32 dilaurate (Kessco PEG 1540 DL, Stepan),PEG-32 dioleate (Kessco) PEG 1540 DO, Stepan), PEG-32 distearate (KesscoPEG 1540 DS, Stepan), PEG-400 dioleate (Cithrol 4D0 series, Croda), andPEG-400 distearate Cithrol 4DS series, Croda). Certain compositions ofthe application can include one or more of the polyethylene glycol fattyacid diesters above.

PEG-fatty acid mono- and all-ester mixtures can be used as excipientsfor the formulation of the compositions provided herein. Examples ofcommercially available PEG-fatty acid mono- and all-ester mixturesinclude: PEG 4-150 mono, dilaurate (Kessco PEG 200-6000 mono, Dilaurate,Stepan), PEG 4-150 mono, dioleate (Kessco PEG 200-6000 mono, Dioleate,Stepan), and PEG 4-150 mono, distearate (Kessco 200-6000 mono,Distearate, Stepan). Certain compositions of the application can includeone or more of the PEG-fatty acid mono- and all-ester mixtures above.

In addition, polyethylene glycol glycerol fatty acid esters can be usedas excipients for the compositions described herein. Examples ofcommercially available polyethylene glycol glycerol fatty acid estersinclude: PEG-20 glyceryl laurate (Tagat) L, Goldschmidt), PEG-30glyceryl laurate (Tagat L2, Goldschmidt), PEG-15 glyceryl laurate(Glycerox L series, Croda), PEG-40 glyceryl laurate (Glycerox L series,Croda), PEG-20 glyceryl stearate (Capmul EMG, ABITEC), and Aldo MS-20KFG, Lonza), PEG-20 glyceryl oleate (Tagat O, Goldschmidt), and PEG-30glyceryl oleate (Tagat 02, Goldschmidt). Certain compositions of theapplication can include one or more of the polyethylene glycol glycerolfatty acid esters above.

Alcohol-oil transesterification products can also be used as excipientsfor the compositions provided herein. Examples of commercially availablealcohol-oil transesterification products include: PEG-3 castor oil(Nikkol C0-3, Nikko), PEG-5, 9, and 16 castor oil (ACCONON CA series,ABITEC), PEG-20 castor oil, (Emalex C-20, Nihon Emulsion), PEG-23 castoroil (Emulgante EL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35castor oil (Incrocas-35, Croda), PEG-38 castor oil (Emulgante EL 65,Condea), PEG-40 castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castoroil (Emalex C-50, Nihon Emulsion), PEG-56 castor oil (Eumulgin PRT 56,Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castoroil, PEG-200 castor oil (Eumulgin PRT 200, Fulcra SA), PEG-5hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castoroil (Cremophor W07, BASF), PEG-10 hydrogenated castor oil (NikkolHCO-10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko),PEG-25 hydrogenated castor oil (Simulsol 1292, Seppic), PEG-30hydrogenated castor oil (Nikkol HCO 30, Nikko), PEG-40 hydrogenatedcastor oil (Cremophor RH 40, BASF), PEG hydrogenated castor oil (CerexELS 450, Auschem Spa), PEG-50 hydrogenated castor oil (Emalex HC-50,Nihon Emulsion), PEG-60 hydrogenated castor oil (Nikkol HCO-60, Nikko),PEG-80 hydrogenated castor oil (Nikkol HCO-80, Nikko), PEG-100hydrogenated castor oil (Nikkol HCO 100, Nikko), PEG-6 corn oil (LabraflM 2125 CS, Gattefosse), PEG-6 almond oil (Labrafil M 1966 CS,Gattefosse), PEG-6 apricot kernel oil (Labrafl M 1944 CS, Gattefosse),PEG-6 olive oil (Labrafil) M 1980 CS, Gattefosse), PEG-6 peanut oil(Labrafil) M 1969 CS, Gattefosse), PEG-6 hydrogenated palm kernel oil(Labrafil M 2130 BS, Gattefosse), PEG-6 palm kernel oil (Labrafil M 2130CS, Gattefosse), PEG-6 triolein (Labrafl M 2735 CS, Gattefosse), PEG-8corn oil (Labrafl WL 2609 BS, Gattefosse), PEG-20 corn glycerides(Crovol M40, Croda), PEG-20 almond glycerides (Crovol A40, Croda),PEG-25 trioleate (TAGAT TO, Goldschmidt), PEG-40 palm kernel oil (CrovolPK-70), PEG-60 corn glycerides (Crovol M70, Croda), PEG-60 almondglycerides (Crovol A70, Croda), PEG-4 caprylic/capric triglyceride(Labrafac( ) Hydro, Gattefos se), PEG-8 caprylic/capric glycerides(Labrasol, Gattefosse), PEG-6 caprylic/capric glycerides (SOFTIGEN767,Huls), lauroyl macrogol-32 glyceride (GELUCIRE 44/14, Gattefosse),stearoyl macrogol glyceride (GELUCIRE 50/13, Gattefosse), mono, di, tri,tetra esters of vegetable oils and sorbitol (SorbitoGlyceride,Gattefosse), pentaerythrityl tetraisostearate (Crodamol PTIS, Croda),pentaerythrityl distearate (Albunol DS, Taiwan Surf.), pentaerythrityltetraoleate (Liponate PO-4, Lipo Chem.), pentaerythrityl tetrastearate(Liponate PS-4, Lipo Chem.), pentaerythrityl tetracaprylate tetracaprate(Liponate PE-810, Lipo Chem.), and pentaerythrityl tetraoctanoate (NilolPentarate 408, NikLo) Also included as oils, are oil-soluble vitamins,such as vitamins A, D, E, K, etc. Derivatives of these vitamins, suchas, tocopheryl PEG-1000 succinate (TPGS, available from Eastman), arealso suitable surfactants for use in the compositions of the presentapplication.

Polyglycerized fatty acids can also be used as excipients for thecompositions provided herein. Commercially available polyglycerizedfatty acids include: polyglyceryl-2 stearate (NikLol DGMS, Nikko),polyglyceryl-2 oleate (Nildol DGMO, Nildco), polyglyceryl-2 isostearate(Nikkol DGMIS, Nikko), polyglyceryl-3 oleate (Caprol 3GO, ABITEC),polyglyceryl-4 oleate (Nildol Tetraglyn 1-O, NikLo), polyglyceryl 4stearate (NikLol Tetraglyn 1-S, Niliko), polyglyceryl-6 oleate (Drewpol6-1 O, Stepan), polyglyceryl-10 laurate (Nildcol Decaglyn 1-L, Nikko),polyglyceryl-10 oleate (NikLol Decaglyn 1-O, Nildo), polyglyceryl-10stearate (Nikkol Decaglyn 1-S, Nikko), polyglyceryl-6 ricinoleate(Nikkol Hexaglyn PR-15, Nikko), polyglyceryl-10 linoleate (NikkolDecaglyn 1-LN, Nikko), polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-O,Nikko), polyglyceryl-3 dioleate (Cremophor G032, BASF), polyglyceryl-3distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (NikkolTetraglyn 5-O, Nikko), polyglyceryl-6 dioleate (Caprol( ) 6G20, ABITEC),polyglyceryl-2 dioleate (Nikkol DGDO, Nikko), polyglyceryl-10 trioleate(Nikkol Decaglyn 3-O, Nikko), polyglyceryl-10 pentaoleate (NikkolDecaglyn 5-O, Nikko), polyglyceryl-10 septaoleate (Nikkol Decaglyn 7-0,Nikko), polyglyceryl-10 tetraoleate (Caprol 1OG40, ABITEC),polyglyceryl-10 decaisostearate (Nikkol Decaglyn 10-IS, Nikko),polyglyceryl-101 decaoleate (Drewpol 10-10 O, Stepan), polyglyceryl-10mono, dioleate (Caprol PGE 860, ABITEC), and polyglycerylpolyricinoleate (Polymuls, Henkel). Certain compositions of theapplication can include one or more of the polyglycerized fatty acidsabove.

In addition, propylene glycol fatty acid esters can be used asexcipients for the compositions provided herein. Examples ofcommercially available propylene glycol fatty acid esters include:propylene glycol monocaprylate (Capryol 90, Gattefosse), propyleneglycol monolaurate (Lauroglycol 90, Gattefosse), propylene glycol oleate(Lutrol OP2000, BASF), propylene glycol myristate (Mirpyl), propyleneglycol monostearate (LIPO PGMS, Lipo Chem.), propylene glycolhydroxystearate, propylene glycol ricinoleate (PROPYMULS, Henkel),propylene glycol isostearate, propylene glycol monooleate (Myverol P-06,Eastman), propylene glycol dicaprylate dicaprate (Captex 200, ABITEC),propylene glycol dioctanoate (Captex 800, ABITEC), propylene glycolcaprylate caprate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate,propylene glycol distearate (Kessco PODS, Stepan), propylene glycoldicaprylate (Nikkol Sefsol 228, Nikko), and propylene glycol dicaprate(Nikkol PDD, Nikko). Certain compositions of the application can includeone or more of the propylene glycol fatty acid esters above.

Mixtures of propylene glycol esters and glycerol esters can also be usedas excipients for the compositions provided herein. One such mixture iscomposed of the oleic acid esters of propylene glycol and glycerol(ARLACEL 186). Examples of these surfactants include: oleic (ATMOS 300,ARLACEL 186, ICI), and stearic (ATMOS 150). Certain compositions of theapplication can include one or more of the mixtures of propylene glycolesters and glycerol esters above.

Further, mono- and diglycerides can be used as excipients for thecompositions provided herein. Examples of commercially available mono-and diglycerides include: monopalmitolein (C16:1) (Larodan), monoelaidin(C18:1) (Larodan), monocaproin (C6) (Larodan), monocaprylin (Larodan),monocaprin (Larodan), monolaurin (Larodan), glyceryl monomyristate (C14)(Nilol MGM, Nikko), glyceryl monooleate (C18:1) (PECEOL, Gattefosse),glyceryl monooleate (Myverol, Eastman), glycerol monooleate/linoleate(OLICINE, Gattefosse), glycerol monolinoleate (Maisine, Gattefosse),glyceryl ricinoleate (Softigen 701, Huls), glyceryl monolaurate (ALDOMLD, Lonza), glycerol monopalmitate (Emalex GMS-P, Nihon), glycerolmonostearate (Capmul GMS, ABITEC), glyceryl mono- and dioleate (CapmulGMO-K, ABITEC), glyceryl palmitic/stearic (CUTINA MD-A, ESTAGEL-G18),glyceryl acetate (Lamegin EE, Grunau GmbH), glyceryl laurate (Imwitor312, Huls), glyceryl citrate/lactate/oleate/linoleate (Imwitor) 375,Huls), glyceryl caprylate (Imwitor 308, Huls), glycerylcaprylate/caprate (Capmul MCM, ABITEC), caprylic acid mono- anddiglycerides (Imwitor 988, Huls), caprylic/capric glycerides (Imwitor742, Huls), mono- and diacetylated monoglycerides (Myvacet 9-45,Eastman), glyceryl monostearate (Aldo MS, Arlacel 129, ICI), lactic acidesters of mono and diglycerides (LAMEGIN GLP, Henkel), dicaproin (C6)(Larodan), dicaprin (C10) (Larodan), dioctanoin (C8) (Larodan),dimyristin (C14) (Larodan), dipalmitin (C16) (Larodan), distearin(Larodan), glyceryl dilaurate (C12) (Capsule GDL, ABITEC), glyceryldioleate (Capmul( ) GDO, ABITEC), glycerol esters of fatty acids(GELUCIRE 39/01, Gattefosse), dipalmitolein (C16:1) (Larodan), 1,2 and1,3-diolein (C18:1) (Larodan), dielaidin (C18:1) (Larodan), anddilinolein (C18:2) (Larodan). Certain compositions of the applicationcan include one or more of the mono- and diglycerides above.

Sterol and sterol derivatives can also be used as excipients for thecompositions provided herein. Examples of commercially available steroland sterol derivatives include: cholesterol, sitosterol, lanosterol,PEG-24 cholesterol ether (Solulan C-24, Amerchol), PEG-30 cholestanol(Phytosterol GENEROL series, Henkel), PEG-25 phytosterol (Nilol BPSH 25,Nikko), PEG-5 soyasterol (Nikkol BPS-5, Nilo), PEG-10 soyasterol (NikLolBPS-10, Niliko), PEG-20 soyasterol (Nikkol BPS-20, NikLo), and PEG-30soyasterol (NikLol BPS-30, NikLo) Certain compositions of theapplication can include one or more of the sterol and sterol derivativesabove.

Polyethylene glycol sorbitan fatty acid esters can also be used asexcipients for the compositions provided herein. Examples ofcommercially available polyethylene glycol sorbitan fatty acid estersinclude: PEG-10 sorbitan laurate (Liposorb L-10, Lipo Chem.), PEG-20sorbitan monolaurate (Tween 20, Atlas/ICI), PEG-4 sorbitan monolaurate(Tween) 21, Atlas/ICI), PEG-80 sorbitan monolaurate (Hodag PSML-80,Calgene), PEG-6 sorbitan monolaurate (NikLol GL-1, NikLo), PEG-20sorbitan monopalmitate (Tween 40, Atlas/ICI), PEG-20 sorbitanmonostearate (Tween 60, Atlas/ICI), PEG-4 sorbitan monostearate (Tween(D 61, Atlas/ICI), PEG-8 sorbitan monostearate (DACOL MS S. Condea),PEG-6 sorbitan monostearate (Nikkol TS106, Nilo), PEG-20 sorbitantristearate (Tween 65, Atlas/ICI), PEG-6 sorbitan tetrastearate (NikLolOS-6, Nildco), PEG-60 sorbitan tetrastearate (NikLol GS-460, Nikko),PEG-5 sorbitan monooleate (Tweed 81, Atlas/ICI), PEG-6 sorbitanmonooleate (Nikkol TO 106, Nikko), PEG-20 sorbitan monooleate (Tweedy80, Atlas/ICI), PEG-40 sorbitan oleate (Emalex ET 5040, Nihon Emulsion),PEG-20 sorbitan trioleate (Tweedy 85, Atlas/ICI), PEG-6 sorbitantetraoleate (Nikkol GO-4, Nikko), PEG-30 sorbitan tetraoleate (NikkolGO-430, Nikko), PEG-40 sorbitan tetraoleate (Nikkol GO-440, Nikko),PEG-20 sorbitan monoisostearate (Tween 120, Atlas/ICI), PEG sorbitolhexaoleate (Atlas G-1086, ICI), polysorbate 80 (Tweed 80, Pharma),polysorbate 85 (Tweed 85, Pharma), polysorbate 20 (Tween 20, Pharma),polysorbate 40 (Tween 40, Pharma), polysorbate 60 (Tween 60, Pharma),and PEG-6 sorbitol hexastearate (Nikkol OS-6, Nikko). Compositions ofthe application can include one or more of the polyethylene glycolsorbitan fatty acid esters above.

In addition, polyethylene glycol alkyl ethers can be used as excipientsfor the compositions described herein. Examples of commerciallyavailable polyethylene glycol alkyl ethers include: PEG-2 oleyl ether,oleth-2 (Brij 92/93, Atlas/ICI), PEG-3 oleyl ether, oleth-3 (Volpo 3,Croda), PEG-5 oleyl ether, oleth-5 (Volpo 5, Croda), PEG-10 oleyl ether,oleth-10 (Volpo 10, Croda), PEG-20 oleyl ether, oleth-20 (Volpo 20,Croda), PEG-4 lauryl ether, laureth-4 (Brij 30, Atlas/ICI), PEG-9 laurylether, PEG-23 lauryl ether, laureth-23 (Brij 35, Atlas/ICI), PEG-2 cetylether (Brij 52, ICI), PEG-10 cetyl ether (Brij 56, ICI), PEG-20 cetylether (BriJ 58, ICI), PEG-2 stearyl ether (Brij 72, ICI), PEG-10 stearylether (Brij 76, ICI), PEG-20 stearyl ether (Brij 78, ICI), and PEG-100stearyl ether (Brij 700, ICI). Compositions of the application caninclude one or more of the polyethylene glycol alkyl ethers above.

Sugar esters can also be used as excipients for the compositionsprovided herein. Examples of commercially available sugar estersinclude: sucrose distearate (SUCRO ESTER 7, Gattefosse), sucrosedistearate/monostearate (SUCRO ESTER 11, Gattefosse), sucrosedipalmitate, sucrose monostearate (Crodesta F-160, Croda), sucrosemonopalmitate (SUCRO ESTER 15, Gattefosse), and sucrose monolaurate(Saccharose monolaurate 1695, Mitsubisbi-Kasei). Compositions of theapplication can include one or more of the sugar esters above.

Polyethylene glycol alkyl phenols are also useful as excipients for thecompositions provided herein. Examples of commercially availablepolyethylene glycol alkyl phenols include: PEG-10-100 nonylphenol series(Triton X series, Rohm & Haas) and PEG-15-100 octylphenol ether series(Triton N-series, Rohm & Haas). Compositions of the application caninclude one or more of the polyethylene glycol alkyl phenols above.

Polyoxyethylene-polyoxypropylene block copolymers can also be used asexcipients for the compositions provided herein. These surfactants areavailable under various trade names, including one or more of SynperonicPE series (ICI), Pluronic series (BASF), Lutrol (BASF), Supronic,Monolan, Pluracare, and Plurodac. The generic term for these copolymersis “poloxamer” (CAS 9003-11-6). These polymers have the formula shownbelow: HO(C₂H₄O)_(a) (C₃H₆O)_(b)(C₂H₄O)_(a)H where “a” and “b” denotethe number of polyoxyethylene and polyoxypropylene units, respectively.These copolymers are available in molecular weights ranging from 1000 to15000 daltons, and with ethylene oxide/propylene oxide ratios between0.1 and 0.8 by weight. Compositions of the application can include oneor more of the polyoxyethylene-polyoxypropylene block copolymers above.

Polyoxyethylenes, such as PEG 300, PEG 400, and PEG 600, can be used asexcipients for the compositions provided herein.

Sorbitan fatty acid esters can also be used as excipients for thecompositions provided herein. Examples of commercially sorbitan fattyacid esters include: sorbitan monolaurate (Span-20, Atlas/ICI), sorbitanmonopalmitate (Span-40, Atlas/ICI), sorbitan monooleate (Span-80,Atlas/ICI), sorbitan monostearate (Span-60, Atlas/ICI), sorbitantrioleate (Span-85, Atlas/ICI), sorbitan sesquioleate (Arlacel-C, ICI),sorbitan tristearate (Span-65, Atlas/ICI), sorbitan monoisostearate(Crill 6, Croda), and sorbitan sesquistearate (Nildcol SS-15, Nikko).Compositions of the application can include one or more of the sorbitanfatty acid esters above.

Esters of lower alcohols (C₂ to C₄) and fatty acids are suitablesurfactants for use in the application. Examples of these surfactantsinclude: ethyl oleate (Crodamol HO, Croda), isopropyl myristate(Crodamol IPM, Croda), isopropyl palmitate (Crodamol IPP, Croda), ethyllinoleate (Nilol VF-E, Nikko), and isopropyl linoleate (NikLol VF-IP,Nikko) Compositions of the application can include one or more of thelower alcohol fatty acid esters above.

In addition, ionic surfactants can be used as excipients for thecompositions provided herein. Examples of useful ionic surfactantsinclude: sodium caproate, sodium caprylate, sodium caprate, sodiumlaurate, sodium myristate, sodium myristolate, sodium palmitate, sodiumpalmitoleate, sodium oleate, sodium ricinoleate, sodium linoleate,sodium linolenate, sodium stearate, sodium lauryl sulfate (dodecyl),sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, sodium cholate, sodium taurocholate, sodiumglycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodiumglycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate,sodium taurochenodeoxycholate, sodium glyco chenodeoxycholate, sodiumcholylsarcosinate, sodium N-methyl taurocholate, egg yolk phosphatides,hydrogenated soy lecithin, dimyristoyl lecithin, lecithin, hydroxylatedlecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin,phosphatidylcholine, phosphatidyl ethanolamine, phosphatidic acid,phosphatidyl glycerol, phosphatidyl serine, diethanolamine,phospholipids, polyoxyethylene-10 oleyl ether phosphate, esterificationproducts of fatty alcohols or fatty alcohol ethoxylates, with phosphoricacid or anhydride, ether carboxylates (by oxidation of terminal OH groupof, fatty alcohol ethoxylates), succinylated monoglycerides, sodiumstearyl fumarate, stearoyl propylene glycol hydrogen succinate,mono/diacetylated tartaric acid esters of mono- and diglycerides, citricacid esters of mono-, diglycerides, glyceryl-lacto esters of fattyacids, acyl lactylates, lactylic esters of fatty acids, sodiumstearoyl-2-lactylate, sodium stearoyl lactylate, alginate salts,propylene glycol alginate, ethoxylated alkyl sulfates, alkyl benzenesulfones, alpha-olefin sulfonates, acyl isethionates, acyl taurates,alkyl glyceryl ether sulfonates, sodium octyl sulfosuccinate, sodiumundecylenamido-MEA-sulfosuccinate, hexadecyl triammonium bromide, decyltrimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecylammonium chloride, alkyl benzyldimethylammonium salts, diisobutylphenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts,betaines (trialkylglycine), lauryl betaine (N-lauryl,N,N-dimethylglycine), and ethoxylated amines (polyoxyethylene-15 coconutamine). For simplicity, typical counter ions are provided above. It willbe appreciated by one skilled in the art, however, that anybioacceptable counter ion can be used. For example, although the fattyacids are shown as sodium salts, other cationic counter ions can also beused, such as, for example, alkali metal cations or ammonium.Compositions of the application can include one or more of the ionicsurfactants above.

The term “penetration enhancers” includes, but is not limited to,chloroform, methyl isobutyl ketone, monoethanolamine, tetradecylmethylsalfoxide, N-(2-Hydroxyethyl)pyrrolidone, dimethyl acetamide,tetrahydrofurfuryl alcohol, Clofibric acid amides, proteolytic enzymes,hexamethylene lauramide, terpenes and sesquiterpenes, alpha-bisbolol,d-limonene, and N,N-diethyl-m-toluamide. One of skill in the art willappreciate that certain penetration enhancers are also useful in thecomposition of the present invention as excipients.

Compositions

In one embodiment of the application, there is provided a stablepharmaceutical composition comprising a luliconazole type antifungalagent or a pharmaceutically acceptable salt thereof, wherein theantifungal agent comprises greater than about 5% by weight of thecomposition. In one aspect, the antifungal agent is greater than about7% by weight of the composition. In another aspect, the antifungal agentis greater than about 10% by weight of the composition. In anotheraspect, the antifungal agent is from about 5% to about 12.5% by weightof the composition.

In one aspect of the application, there is provided a stablepharmaceutical composition comprising luliconazole or a luliconazoletype antifungal agent or a pharmaceutically acceptable salt thereofwherein the antifungal agent comprises greater than about 5% by weightof the composition. In one aspect, the antifungal agent is greater thanabout 7% by weight of the composition. In another aspect, the antifungalagent is greater than about 10% by weight of the composition. In yetanother aspect, the antifungal agent is from about 5% to about 12.5% byweight of the composition. In yet another aspect, the antifungal agentis about 10% by weight of the composition.

In another aspect, the composition is stable for at least 4 weeks. Inanother aspect, the composition is stable for at least 4 weeks at atemperature of about 4° C.

In another aspect, the compositions provided herein comprise at leastone excipient selected from the group consisting of an alcohol, aketone, a polar aprotic solvent and an ethylene glycol derivative. Inone aspect, the compositions described herein comprise at least oneexcipient selected from the group consisting of an alcohol, a ketone, apolar aprotic solvent and an ethylene glycol derivative wherein theexcipient is present in the composition in an amount provided in TableA. It is understood that the compositions may include more than oneexcipient selected from the group consisting of an alcohol, a ketone, apolar aprotic solvent and an ethylene glycol derivative, including morethan one excipient of the same class (e.g., the composition may comprisetwo or more different alcohols, such as benzyl alcohol and ethanol). Itis also understood that such compositions may comprise luliconazole inamounts described herein, including but not limited to from about any of5 or 8 or 10 or 12 weight percent to about 15 weight percent; from about5 weight percent to about any of 8 or 10 or 12 weight percent; fromabout 8 weight percent to about 12 weight percent; from about 9 weightpercent to about 11 weight percent; about any of 5 or 8 or 10 or 12 or15 weight percent; at least about any of 5 or 8 or 10 or 12 or 15 weightpercent; at least 0.01 weight percent but not more than about 15 weightpercent.

TABLE A Exemplary Weight Percent of Certain Components (Excipients) foruse in Luliconzole Formulations Formulation Component Weight Percent ofComponent in Formulation an alcohol (e.g., ethanol) From about 20 toabout 80; from about 25 to about 75; from about 30 to about 70; fromabout 35 to about 65; from about 30 or about 40 to about 60; from about40 to about 50; from about 35 or about 45 to about 55; about any of 20or 25 or 30 or 35 or 40 or 45 or 50 or 55 or 60 or 65 or 70 or 75 or 80weight percent or more; and at least about any of 20 or 25 or 30 or 35or 40 or 45 or 50 or 55 or 60 or 65 or 70 or 75 or 80 weight percent. analcohol (e.g., benzyl From 0.01 to about any of 2 or 4 or 6 or 8 or 10;from about any alcohol) of 1 or 2 or 4 to about 10; from about 6 toabout 10; from about 8 to about 10; about any of 1 or 2 or 3 or 4 or 5or 6 or 7 or 8 or 9 or 10; at least about any of 1 or 2 or 3 or 4 or 5or 6 or 7 or 8 or 9 or 10; at least 0.01 but not more than about any of10 or 8 or 6 or 5 or 4 or 3 or 2 weight percent. a ketone (e.g.,acetone) From 0.01 to about any of 5 or 10 or 15 or 20 or 25; from about1 to about 20 or about 25; from about 5 to about 15 or about 25; fromabout 8 to about 15; from about 10 to about 15 or about 25; from about11 to about 13; about any of 1 or 5 or 8 or 10 or 12 or 15 or 20 or 25;at least about any of 1 or 5 or 8 or 10 or 12 or 15 or 20 or 25; atleast 0.01 but not more than about any of 25 or 20 or 15 or 10 or 5weight percent. a polar aprotic solvent From 0.01 to about any of 3 or 5or 8 or 10 or 15 or 20; from (e.g., propylene about 1 to about 15 orabout 20; from about 5 to about 20; from carbonate) about 10 to about20; from about 15 to about 20; from about 3 to about 8 or about 10; fromabout 4 to about 6; about any of about 1 or 3 or 5 or 8 or 10 or 12 or15 or 20 or 25; at least about any of 1 or 3 or 5 or 8 or 10 or 12 or 15or 20 or 25; at least 0.01 but not more than about 25 or 20 or 15 or 10or 5 weight percent. ethylene glycol derivative. From about any of 1 or10 or 20 or 30 or 40 to about 50; from (e.g., a diethylene glycol about1 to about any of 10 or 20 or 30 or 40; from about 10 to monosubstitutedether of about 40; from about 15 to about 35; from about 20 or about 30;the formula from about 20 to about 25; about any of 1 or 5 or 10 or 15or 20 HOCH₂CH₂OCH₂CH₂OR, or 25 or 30 or 35 or 40 or 45 or 50; at leastabout any of or 5 or 10 where R is an alkyl group or 15 or 20 or 25 or30 or 35 or 40 or 45 or 50; at least 0.01 but having 1-6 carbon atomsnot more than about any of 40 or 30 or 25 or 20 or 15 or 10 or 5 (e.g.,ethyl)) weight percent.

It is understood that components of a luliconazole composition may bepresent in amounts that result in one or more advantageous properties asdescribed herein. In one variation the amounts are as described in TableA. Thus, the pharmaceutical compositions described may comprise theformulation components in a weight percentage detailed herein, the sameas if each and every combination of component and weight percent werespecifically and individually listed. For example, in a luliconazolecomposition comprising at least one of an alcohol, a ketone, a polaraprotic solvent and an ethylene glycol derivative, in one aspectluliconazole is present in the composition in about 10 weight percentand the alcohol, ketone, polar aprotic solvent or an ethylene glycolderivative is present in an amount provided in Table A. In one aspect, acomposition is provided wherein the composition comprises from about anyof 5 or 8 or 10 or 12 weight percent to about 15 weight percentluliconazole and an alcohol (such as ethanol and/or benzyl alcohol) inan amount described in Table A. In a particular variation, thecomposition comprises both ethanol and benzyl alcohol. In one aspect, acomposition is provided wherein the composition comprises from about anyof 5 or 8 or 10 or 12 weight percent to about 15 weight percentluliconazole and a ketone (such as acetone, ethylmethyl ketone andisobutyl ketone) in an amount described in Table A. In one aspect, acomposition is provided wherein the composition comprises from about anyof 5 or 8 or 10 or 12 weight percent to about 15 weight percentluliconazole and a polar aprotic solvent (such as propylene carbonate,ethylene carbonate and glycerin carbonate) in an amount described inTable A. In a particular variation, the polar aprotic solvent is otherthan NMP. In one aspect, a composition is provided wherein thecomposition comprises from about any of 5 or 8 or 10 or 12 weightpercent to about 15 weight percent luliconazole and an ethylene glycolderivative (such as diethylene glycol monoethyl ether) in an amountdescribed in Table A.

In another aspect, the compositions provided herein comprise at leasttwo excipients selected from the group consisting of an alcohol, aketone, a polar aprotic solvent and an ethylene glycol derivative. It isunderstood that when at least two excipients selected from the groupconsisting of an alcohol, a ketone, a polar aprotic solvent and anethylene glycol derivative are components of a luliconazole composition,such components may be present in amounts that result in one or moreadvantageous properties as described herein. In one variation theamounts are as described in Table A. Thus, the pharmaceuticalcompositions described may comprise two or more of an alcohol, a ketone,a polar aprotic solvent and an ethylene glycol derivative in a weightpercentage detailed herein, the same as if each and every combination ofcomponent and weight percent were specifically and individually listed.For example, in a luliconazole composition comprising at least two of analcohol, a ketone, a polar aprotic solvent and an ethylene glycolderivative, in one aspect luliconazole is present in the composition inabout 10 weight percent and the two components selected from an alcohol,ketone, polar aprotic solvent or an ethylene glycol derivative arepresent in an amount provided in Table A. In one aspect, a compositionis provided wherein the composition comprises from about any of 5 or 8or 10 or 12 weight percent to about 15 weight percent luliconazole andtwo or more alcohols (such as ethanol and benzyl alcohol) in an amountdescribed in Table A. In a particular variation, ethanol is provided inan amount specified in the first row of Table A and benzyl alcohol isprovided in an amount specified in the second row of Table A. In oneaspect, a composition is provided wherein the composition comprises fromabout any of 5 or 8 or 10 or 12 weight percent to about 15 weightpercent luliconazole; and, in an amount described in Table A, acombination of excipients selected from: (i) an alcohol and a ketone;(ii) an alcohol and a polar aprotic solvent; (iii) an alcohol and anethylene glycol derivative; (iv) a ketone and a polar aprotic solvent;(v) a ketone and an ethylene glycol derivative; and (vi) a polar aproticsolvent and an ethylene glycol derivative. In a particular variation,the alcohol is ethanol and/or benzyl alcohol; the ketone is acetone,ethylmethyl ketone and isobutyl ketone; the polar aprotic solvent ispropylene carbonate, ethylene carbonate or glycerin carbonate and theethylene glycol derivative is a diethyleneglycol monosubstituted etherof the formula HOCH₂CH₂OCH₂CH₂OR, where R is an alkyl group having 1-6carbon atoms (e.g., ethyl). In a more particular variation, the alcoholis ethanol and/or benzyl alcohol; the ketone is acetone; the polaraprotic solvent is propylene carbonate and the ethylene glycolderivative is a diethyleneglycol monosubstituted ether of the formulaHOCH₂CH₂OCH₂CH₂OR, where R is ethyl (diethyleneglycol monoethyl ether).

In another aspect, the compositions provided herein comprise at leastthree excipients selected from the group consisting of an alcohol, aketone, a polar aprotic solvent and an ethylene glycol derivative. It isunderstood that when at least three excipients selected from the groupconsisting of an alcohol, a ketone, a polar aprotic solvent and anethylene glycol derivative are components of a luliconazole composition,such components may be present in amounts that result in one or moreadvantageous properties as described herein. In one variation theamounts are as described in Table A. Thus, the pharmaceuticalcompositions described may comprise three or more of an alcohol, aketone, a polar aprotic solvent and an ethylene glycol derivative in aweight percentage detailed herein, the same as if each and everycombination of component and weight percent were specifically andindividually listed. For example, in a luliconazole compositioncomprising at least three of an alcohol, a ketone, a polar aproticsolvent and an ethylene glycol derivative, in one aspect luliconazole ispresent in the composition in about 10 weight percent and the threecomponents selected from an alcohol, ketone, polar aprotic solvent or anethylene glycol derivative are present in an amount provided in Table A.In one aspect, a composition is provided wherein the compositioncomprises from about any of 5 or 8 or 10 or 12 weight percent to about15 weight percent luliconazole and two or more alcohols (such as ethanoland benzyl alcohol) in an amount described in Table A. In a particularvariation, ethanol is provided in an amount specified in the first rowof Table A and benzyl alcohol is provided in an amount specified in thesecond row of Table A. In one aspect, a composition is provided whereinthe composition comprises from about any of 5 or 8 or 10 or 12 weightpercent to about 15 weight percent luliconazole; and, in any amountdescribed in Table A, a combination of excipients selected from: (i) analcohol, a ketone and a polar aprotic solvent; (ii) an alcohol, a ketoneand an ethylene glycol derivative; (iii) an alcohol, a polar aproticsolvent and an ethylene glycol derivative; and (iv) a ketone, a polaraprotic solvent and an ethylene glycol derivative. In a particularvariation, the alcohol is ethanol and/or benzyl alcohol; the ketone isacetone, ethylmethyl ketone and isobutyl ketone; the polar aproticsolvent is propylene carbonate, ethylene carbonate or glycerin carbonateand the ethylene glycol derivative is a diethyleneglycol monosubstitutedether of the formula HOCH₂CH₂OCH₂CH₂OR, where R is an alkyl group having1-6 carbon atoms (e.g., ethyl). In a more particular variation, thealcohol is ethanol and/or benzyl alcohol; the ketone is acetone; thepolar aprotic solvent is propylene carbonate and the ethylene glycolderivative is a diethyleneglycol monosubstituted ether of the formulaHOCH₂CH₂OCH₂CH₂OR, where R is ethyl.

In another aspect, the compositions provided herein comprise each of theexcipients selected from the group consisting of an alcohol, a ketone, apolar aprotic solvent and an ethylene glycol derivative. It isunderstood that when each of the excipients selected from the groupconsisting of an alcohol, a ketone, a polar aprotic solvent and anethylene glycol derivative are components of a luliconazole composition,such components may be present in amounts that result in one or moreadvantageous properties as described herein. In one variation theamounts are as described in Table A. Thus, the pharmaceuticalcompositions described may comprise an alcohol, a ketone, a polaraprotic solvent and an ethylene glycol derivative in a weight percentagedetailed herein, the same as if each and every combination of componentand weight percent were specifically and individually listed. Forexample, in a luliconazole composition comprising each of an alcohol, aketone, a polar aprotic solvent and an ethylene glycol derivative, inone aspect luliconazole is present in the composition in about 10 weightpercent and the alcohol, ketone, polar aprotic solvent and ethyleneglycol derivative are present in an amount provided in Table A. In oneaspect, a composition is provided wherein the composition comprises fromabout any of 5 or 8 or 10 or 12 weight percent to about 15 weightpercent luliconazole and two or more alcohols (such as ethanol andbenzyl alcohol) in an amount described in Table A. In a particularvariation, ethanol is provided in an amount specified in the first rowof Table A and benzyl alcohol is provided in an amount specified in thesecond row of Table A. In one aspect, a composition is provided whereinthe composition comprises from about any of 5 or 8 or 10 or 12 weightpercent to about 15 weight percent luliconazole; and, in an amountdescribed in Table A, each of an alcohol, a ketone a polar aproticsolvent and an ethylene glycol derivative. In a particular variation,the alcohol is ethanol and/or benzyl alcohol; the ketone is acetone,ethylmethyl ketone and isobutyl ketone; the polar aprotic solvent ispropylene carbonate, ethylene carbonate or glycerin carbonate and theethylene glycol derivative is a diethyleneglycol monosubstituted etherof the formula HOCH₂CH₂OCH₂CH₂OR, where R is an alkyl group having 1-6carbon atoms (e.g., ethyl). In a more particular variation, the alcoholis ethanol and/or benzyl alcohol; the ketone is acetone; the polaraprotic solvent is propylene carbonate and the ethylene glycolderivative is a diethyleneglycol monosubstituted ether of the formulaHOCH₂CH₂OCH₂CH₂OR, where R is ethyl.

In one embodiment, the luliconazole compositions (including but notlimited to the compositions comprising at least one or two or three oreach of an alcohol, a ketone, a polar aprotic solvent and an ethyleneglycol derivative) further comprise a film forming agent, such as amaleic anhydride/methyl vinyl ether copolymer as described herein. Inone aspect, the film forming agent is present in from 0.01 weightpercent to about any of 1 or 2 or 4 or 6 or 8 or 10 weight percent orfrom about 5 to about 1 weight percent or from about 1 to about 3 weightpercent or in about any of 0.5 or 1 or 2 or 3 or 5 weight percent or atleast about any of 0.01 or 0.5 or 1 or 2 or 3 or 5.

In one embodiment, the luliconazole compositions (including but notlimited to the compositions comprising at least one or two or three oreach of an alcohol, a ketone, a polar aprotic solvent and an ethyleneglycol derivative), and optionally a film forming agent, in one aspectis substantially anhydrous.

In another embodiment, the luliconazole compositions (including but notlimited to the compositions comprising at least one or two or three oreach of an alcohol, a ketone, a polar aprotic solvent and an ethyleneglycol derivative), and optionally a film forming agent, in one aspectprovide a clear solution without evidence of crystal formation uponvisual inspection after 6 months of storage at any of 5° C., 25° C. and40° C.

In another embodiment, the luliconazole compositions (including but notlimited to the compositions comprising at least one or two or three oreach of an alcohol, a ketone, a polar aprotic solvent and an ethyleneglycol derivative), and optionally a film forming agent, in one aspectcontain at least about 95% of the theoretical maximum amount ofluliconazole after 6 months of storage at any of 5° C., 25° C. and 40°C.

In another embodiment, the luliconazole compositions (including but notlimited to the compositions comprising at least one or two or three oreach of an alcohol, a ketone, a polar aprotic solvent and an ethyleneglycol derivative), and optionally a film forming agent, in one aspectprovide a clear solution without evidence of crystal formation uponvisual inspection after 6 months of storage at any of 5° C., 25° C. and40° C. and contain at least about 95% of the theoretical maximum amountof luliconazole after 6 months of storage at any of 5° C., 25° C. and40° C.

In another embodiment, the luliconazole compositions (including but notlimited to the compositions comprising at least one or two or three oreach of an alcohol, a ketone, a polar aprotic solvent and an ethyleneglycol derivative), and optionally a film forming agent, in one exhibitefficacy against fungal infections, such as onychomycosis. In oneaspect, the compositions provided herein eradicates at least 80% of afungal infection of the nail after 14 days of treatment, as measured bythe recovery of less than 20% of the theoretical amount of recoverableATP from the fungus. Preferably, such compositions result in both high(e.g., greater than any of 80% or 85% or 90% or 95% or 98% or 100%)mycological cure and clinical cure rates.

In another embodiment, the luliconazole compositions (including but notlimited to the compositions comprising at least one or two or three oreach of an alcohol, a ketone, a polar aprotic solvent and an ethyleneglycol derivative) and optionally a film forming agent, in one aspectthe composition exhibits penetration through a nail, such as a toenail.

In another aspect, the alcohol is benzyl alcohol, ethanol or acombination thereof. In another aspect, the ethanol is from about 5% toabout 80% by weight of the composition. In another aspect, the ethanolis from about 35% to about 60% by weight of the composition. In anotheraspect, the ethanol is from about 40% to about 48% by weight of thecomposition. In another aspect, the benzyl alcohol is from about 0.5% toabout 50% by weight of the composition. In another aspect, the benzylalcohol is from about 1% to about 15% by weight of the composition. Inanother aspect, the benzyl alcohol is from about 1% to about 6% byweight of the composition.

In another aspect, the ketone is acetone. In another aspect, the acetoneis from about 0.5% to about 50% by weight of the composition. In anotheraspect, the acetone is from about 5% to about 15% by weight of thecomposition. In another aspect, the acetone is from about 10% to about14% by weight of the composition.

In another aspect, the polar aprotic solvent is propylene carbonate. Inanother aspect, the propylene carbonate is from about 0.5% to about 50%by weight of the composition. In another aspect, the propylene carbonateis from about 5% to about 15% by weight of the composition. In anotheraspect, the propylene carbonate is from about 3% to about 7% by weightof the composition.

In another aspect, the ethylene glycol derivative is diethylene glycolmonoethyl ether (such as Transcutol™ P). In another aspect thediethylene glycol monoethyl ether (such as Transcutol™ P) is from about0.5% to about 70% by weight of the composition. In another aspect, thediethylene glycol monoethyl ether (such as Transcutol™ P) is from about5% to about 30% by weight of the composition. In another aspect, thediethylene glycol monoethyl ether (such as Transcutol™ P) is from about23% to about 27% by weight of the composition.

In another aspect, the compositions provided herein comprise about 10%of the antifungal agent, about 2% benzyl alcohol, about 12% acetone andabout 25% diethylene glycol monoethyl ether (such as Transcutol™ P). Inanother aspect, the compositions provided herein comprise about 12.5%active agent, about 4% benzyl alcohol, about 12% acetone and about 25%diethylene glycol monoethyl ether (such as Transcutol™ P).

In another aspect, the antifungal agent is luliconazole. In anotheraspect, the antifungal agent is lanoconazole of the formula:

In another aspect, luliconazole is about 10% by weight of thecomposition.

Embodiments that contain luliconazole can apply to lanoconazole.

In another aspect, the compositions provided herein comprise at leastone excipient, or alternatively at least two excipients, oralternatively at least three excipients selected from the groupconsisting of an alcohol, a ketone, a polar aprotic solvent, an ethyleneglycol derivative, an alpha hydroxyl acid or its salt, a diester of adibasic acid, and a surface active agent.

In another aspect, the compositions provided herein comprise at leastone excipient, or alternatively at least two excipients, oralternatively at least three excipients selected from the groupconsisting of an alcohol, a ketone, a polar aprotic solvent and anethylene glycol derivative. Within this aspect, in certain otheraspects, the compositions of the present application further comprise atleast one excipient or alternatively at least two excipients selectedfrom the group consisting of an alpha-hydroxy acid, a diester of adibasic acid, and a surface active agent.

In another aspect, the compositions provided herein further comprise afilm-forming agent. In another aspect, the film-forming agent ismethylvinyl ether-maleic anhydride (Gantrez).

In another aspect, the compositions provided herein are gels or creamssuitable for topical administration.

Certain excipients useful in the compositions of the present applicationare disclosed below.

Alcohols

In one aspect, the alcohol, useful as an excipient in the compositionsof the present application, is ethyl alcohol selected from the groupconsisting of dehydrated ethyl alcohol, denatured ethyl alcohol, dilutedethyl alcohol (50% aqueous), SD alcohol 3a, SD alcohol 40, SD alcohol40-2, SD alcohol 40b. As used herein, SD refers to specially denaturedalcohol.

In another aspect, the alcohol is a short chain aliphatic alcohol. Inanother aspect, the short chain aliphatic alcohol is selected from thegroup consisting of butyl alcohol, isopropyl alcohol, methyl alcohol,phenoxyethanol and tert butyl alcohol. In another aspect, the alcohol isalpha-terpinol. In another aspect, the alcohol is a long chain fattyalcohol. In another aspect, the long chain fatty alcohol is selectedfrom the group consisting of ceteryl alcohol, cetyl alcohol, docosanol,myristyl alcohol, oleyl alcohol, and stearyl alcohol. In another aspect,the alcohol is selected from alpha-tocopherol, amerchol CAB,chlorobutanol (3,3,3,-trichloromethyl-2,2-dimethylethanol), hydroxyethylcellulose, hydroxymethyl cellulose, hydroxyoctacosanyl hydroxystearate,hydroxypropyl cellulose (e.g., Krucel® hydroxypropyl cellulose),isostearyl alcohol, menthol, N,N-bis(2-hydroxyethyl)stearamide, octylhydroxystearate, sorbitol, N-(2-Hydroxyethyl)pyrrolidone, andtetrahydrofurfuryl alcohol. In another aspect, the alcohol is an aminoalcohol. In another aspect, the amino alcohol is selected from the groupconsisting of 2-amino-2-methyl-1-propanol, diethanolamine,di-isopropanolamine, and monoethanolamine.

In another aspect, the alcohol used in the compositions of the presentapplication is a C₁-C₂₅ alkanol. In another aspect, the alcohol is aC₁-C₁₂ alkanol. In another aspect, the alcohol is a C₁-C₇ alkanol.Within these aspects, the alcohol is a primary alcohol, a secondaryalcohol, or a tertiary alcohol. The carbon backbone of the alkanol isoptionally substituted with a phenyl, amino, alkoxy, phenoxy or a halogroup. In another aspect, the alcohol used in the compositions of thepresent application has a formula C₃-C₈ cycloalkyl-OH or C₃-C₈heterocyclyl-OH, provided that the hydroxyl group is not attached to acarbon atom that is attached to a heteroatom.

In another aspect, the alcohol is benzyl alcohol. In another aspect, thealcohol is 2,4-dichlorobenzyl alcohol.

In certain aspects, the content of alcohols in the pharmaceuticalcomposition of the present application is about 5 to about 80%, about 10to about 70%, about 20 to about 60%, about 30 to about 50%, about 35 toabout 55%, or about 50%, by mass, with respect to the total amount ofthe pharmaceutical composition.

Ethylene Glycol Derivatives

In one aspect, the ethylene glycol derivative is a diol or a diolderivative selected from the group consisting of butylene glycol,dipropylene glycol, ethylene glycol, hexylene glycol, and propyleneglycol. In another aspect, the ethylene glycol derivative is a diolderivative selected from the group consisting of diethylene glycolmonomethyl ether, diethylene glycol monoethyl ether (such asTranscutol™), ethyl hexanediol, propylene glycol monolaurate, propyleneglycol monostearate, propylene glycol palmitostearate and propyleneglycol ricinoleate.

In one embodiment, the formulation comprises a diethylene glycolmonosubstituted ether. In another embodiment, the diethylene glycolmonosubstituted ether is a compound of the formula HOCH₂CH₂OCH₂CH₂OR,wherein R is selected from the group consisting of a linear alkyl grouphaving 1-6 carbon atoms, a branched alkyl group having 2-12 carbonatoms, a cycloalkyl group having 3-17 carbon atoms, a fluorinated linearalkyl group having 2-12 carbon atoms, a fluorinated branched alkyl grouphaving 2-12 carbon atoms, and a fluorinated cycloalkyl group having 3-17carbon atoms, an aryl group, an aralkyl group, an alkaryl group, acycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkalkenylgroup, an alkenylalkyl group, an alkynyl group, an alkalkynyl group, analkynylalkyl group, a trifluoropropyl group, a cyanopropyl group, anacryloyl group, an arylacryloyl group, an acryloylaryl group, analkylacyl group, an arylacyl group, an alkylenylacyl group and analkynylacyl group, and combinations thereof. In another embodiment, R isa linear alkyl group having 1-6 carbon atoms or a branched alkyl grouphaving 2-12 carbon atoms. In another embodiment, R is a linear alkylgroup having 1-6 carbon atoms. In another embodiment, R is a linearalkyl group having 2 to 3 carbon atoms. In another embodiment, R isethyl, which corresponds to ethoxy diglycol reagent (also known asdiethylene glycol monoethyl ether and 2-(2-ethoxyethoxy)ethanol), shownbelow.

In another embodiment, the formulation comprises a polyoxylglyceride. Inone embodiment, the polyoxylglyceride is a caprylocaproyl, linoleoyl,oleoyl, lauroyl, or stearoyl polyoxylglyceride. In another embodiment,the polyoxylglyceride is lauroyl polyoxyl-32 glycerides, stearoylpolyoxyl-32 glycerides, medium chain triglycerides, oleoyl polyoxyl-6glycerides, linoleoyl polyoxyl-6 glycerides, lauroyl polyoxyl-6glycerides, or caprylocaproyl polyoxyl-8-glycerides. Suchpolyoxylglycerides are available from Gattefosse (Canada) under thetradenames Labrasol, Labrafil, and Gelucire.

In yet another aspect, the ethylene glycol derivative is a polyolselected from the group consisting of glycerin, glyceryl acetate,glyceryl citrate, glyceryl isostearate, glyceryl laurate, glycerylmonostearate, glyceryl oleate, glyceryl palmitate, glyceryl ricinoleate,glyceryl stearate-laureth-23, glyceryl stearate SE, glycerylstearate/PEG-100 stearate and 1,2,6-hexanetriol.

In another aspect, the ethylene glycol derivative has the formulaR-alkylene-R or R-heteroalkylene-R wherein R is selected from the groupconsisting of hydroxy, alkoxy, phenoxy, alkylcarbonyloxy andarylcarbonyloxy, and wherein the alkylene or heteroalkylene moiety isoptionally substituted with a hydroxyl, alkoxy, phenoxy,alkylcarbonyloxy and arylcarbonyloxy group, provided however that, 2heteroatoms (for example, 2 oxygen atoms) are not attached to the samecarbon atom. Within this aspect, the alkylene moiety is C₁-C₇ alkylene,C₁-C₅ alkylene, or C₁-C₃ alkylene. In another related aspect, theheteroalkylene moiety is C₁-C₇ heteroalkylene, C₁-C₅ heteroalkylene orC₁-C₃ heteroalkylene.

In another aspect, the ethylene glycol derivative is a polyethyleneglycol (PEG) moiety selected from the group consisting of polyethyleneglycol 1000, polyethylene glycol 1500, polyethylene glycol 1540,polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol300-1600, polyethylene glycol 3350, polyethylene glycol 400,polyethylene glycol 4000, polyethylene glycol 540, polyethylene glycol600, polyethylene glycol 6000, polyethylene glycol 8000, polyethyleneglycol 900, polyoxyethylene-polyoxypropylene 1800 and polyoxyethylenealcohols.

In another aspect, the ethylene glycol derivative is a PEG derivativeselected from the group consisting of ceteth-2, ceteth-10, ceteth-20,ceteth-23, dimethicone copolyol, PEG 6-32 stearate/glycol stearate,PEG-22 methyl ether/dodecyl glycol copolymer, PEG-25 propylene glycolstearate, PEG-45/dodecyl glycol copolymer, peglicol-5-oleate, pegoxol 7stearate, PPG-12/SMDI copolymer, polypropylene glycol (PPG)-15 stearylether, PPG-20 methyl glucose ether distearate, PPG-26 oleate,steareth-10, steareth-100, steareth-2, steareth-20 and steareth-21.

In another aspect, the ethylene glycol derivative is a PEG derivativeselected from the group consisting of poloxamer 124, poloxamer 181,poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407,polyoxyethylene fatty acid esters, polyoxyethylene propylene,methoxypolyoxyethylene glycol 350 and tyloxapol.

In another aspect, the ethylene glycol derivative is a PEG derivativeselected from nonoxynol-15, nonoxynol-15, nonoxynol-9, octoxynol-1 andoctoxynol-9.

In another aspect, the ethylene glycol derivative is a PEG derivativeselected from polyoxyl 100 glyceryl stearate, polyoxyl 100 stearate,polyoxyl 15 cocamine, polyoxyl 150 distearate, polyoxyl 2 stearate,polyoxyl 4 dilaurate, polyoxyl 40 hydrogenated castor oil, polyoxyl 40stearate, polyoxyl 400 stearate, polyoxyl 50 stearate, polyoxyl 6 andpolyoxyl 32 palmitostearate, polyoxyl 6 isostearate, polyoxyl 60hydrogenated castor oil, polyoxyl 75 lanolin, polyoxyl 8 laurate,polyoxyl 8 stearate, polyoxyl distearate, polyoxyl glyceryl stearate,polyoxyl lanolin and polyoxyl stearate.

In certain aspects, the content of ethylene glycol derivatives in thepharmaceutical composition of the present application is about 1 toabout 50%, about 5 to about 45%, about 10 to about 40%, about 15 toabout 35%, about 20 to about 30%, or about 25%, by mass, with respect tothe total amount of the pharmaceutical composition.

Ketones

In another aspect, the ketone is selected from the group consisting ofacetone, ethyl methyl ketone and methyl isobutyl ketone.

In certain aspects, the content of alcohols in the pharmaceuticalcomposition of the present application is about 1 to about 40%, about 5to about 35%, about 10 to about 30%, or about 15%, by mass, with respectto the total amount of the pharmaceutical composition.

Polar Aprotic Solvents

In another aspect, the polar aprotic solvent is selected from the groupconsisting of propylene carbonate, ethylene carbonate, and glycerincarbonate. In another aspect, the polar aprotic solvent is selected fromthe group consisting of N-methylpyrrolidone, dimethyl acetamide andDMSO.

In certain aspects, the content of alcohols in the pharmaceuticalcomposition of the present application is about 1 to about 50%, about 2to about 40%, about 3 to about 30%, about 4 to about 20%, or about 5 toabout 10%, by mass, with respect to the total amount of thepharmaceutical composition.

Alpha-Hydroxycarboxylic Acids and their Salts

In certain other aspects, the alpha-hydroxycarboxylic acid is analpha-hydroxycarboxylic acid having from 2 to 25, from 5 to 20, from 10to 15, and from 2 to 5 carbon atoms. The alkylene backbone of such acidscan be suitably substituted. Suitable substituents include, withoutlimitation, alkoxy, amino, halo, hydroxy and phenoxy groups. In anotheraspect, the alpha-hydroxycarboxylic acid is selected from lactic acid,glycolic acid and malic acid. Salts of the alpha-hydroxycarboxylic acidsinclude, without limitation, sodium salt and potassium salt; alkalineearth metal salts, such as calcium salt and magnesium salt; amine salts,such as ammonium salt, triethylamine salt, and triethanol amine salt;and basic amino acid salts, such as arginine salt and lysine salt.

In certain aspects, the content of alpha-hydroxycarboxylic acids in thepharmaceutical composition of the present application is about 0.1 toabout 20% by mass, or about 1 to about 10% by mass, with respect to thetotal amount of the pharmaceutical composition.

In certain other aspects, the mass ratio of alpha-hydroxycarboxylic acidor its salt to luliconazole or luliconazole type antifungal agent isabout 0.1 to about 10, about 0.5 to about 5, or about 0.8 to 2.

Diesters of Dibasic Acids

In certain aspects, the diesters of dibasic acids comprise, as part ofthe ester moiety, alcohols having from 1 to 25, from 5 to 20, from 10 to15, and from 1 to 4 carbon atoms. In certain other aspects, the alcoholuseful as part of the diester of a dibasic acid is selected from thegroup consisting of methyl alcohol, ethyl alcohol, propyl alcohol,isopropyl alcohol, butyl alcohol, isobutyl alcohol and tert-butylalcohol. Any polyol, such as an ethylene glycol and a propylene glycolcan be used as the alcohol having 1 to 4 carbon atoms.

In certain aspect, the dibasic acids are those having from 1 to 25, from5 to 20, from 10 to 15, and from 1 to 10 carbon atoms. In certain otheraspects, the dibasic acid is selected from the group consisting ofadipic acid, sebacic acid, oxalic acid and carbonic acid. In anotheraspect, a diester of the dibasic acid is selected from the groupconsisting of diethyl adipate, di-isopropyl adipate, diethyl sebacate,and di-isopropyl sebacate.

In certain aspects, the overall content of the diesters of dibasic acidsused in the compositions of the invention is about 1 to about 30% bymass or about 5 to about 15% by mass, with respect to the total amountof the pharmaceutical composition.

One of skilled in the art, upon this disclosure will appreciate thatpenetration enhancers are useful in the compositions of the presentinvention in accordance with the present invention.

Film-forming agents are also useful in the practice of the presentinvention, including for example maleic anhydride/methyl vinyl ethercopolymers such as Gantrez copolymers sold by Internationals SpecialtyProducts (Wayne, N.J.), as well as the ethyl, isopropyl, and butylesters of these copolymers, and maleic anhydride/butyl vinyl ethercopolymers. Hydroxyalkylcellulose polymers, such as Krucel®hydroxypropyl cellulose sold by Hercules Incorporated (Wilmington, Del.)may also be used as a film-forming agent.

Certain compositions of the present invention are tabulated below.

While the compositions tabulated below include luliconazole as theantifungal agent, one of ordinary skill in the art will appreciate, uponreading this disclosure, that similar compositions includinglanoconazole instead of luliconazole is within the scope of the presentinvention. Although grades of components are indicated in somevariations, it is understood that other grades may be used. In addition,although Transcutol™ P is referred to in certain instances, such as thetables below, it is understood that compositions comprising diethyleneglycol monoethyl ether may be used. In addition, although Gantez isreferred to in certain instances, it is understood that compositionscomprising butyl ester of PVM/MA copolymer may be used (such as butylester of PVM/MA copolymer, 38-52% isopropyl alcohol, <10% butylalcohol). In addition, it is understood that reference to Alcohol (200Proof) includes and intends ethanol.

TABLE 1a % % % % % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wtwt/wt wt/wt wt/wt wt/wt wt/wt Ethanol (200   5-80  10-70  20-60 35-45 40-50  40-50  40-50  40-48 45-47 40-42 Proof) USP Benzyl 0.5-50 0.5-400.5-30 1-15 1-10 1-10 1-10 1-6 1-3 3-6 alcohol, USP Propylene 0.5-500.5-40 0.5-30 5-15 5-10 5-10 5-10 3-7 4-6 4-6 Carbonate NF Acetone NF0.5-50 0.5-40 0.5-30 5-15 5-10 5-10 5-10 10-14 11-13 11-13 Transcutol ™P 0.5-70 0.5-60 0.5-50 5-30 10-30  15-30  20-30  23-27 24-26 24-26Luliconazole   5-15   5-15   5-15 5-15 6-13 8-12 9-11 10-13  9-11 11-13

TABLE 2a % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wt wt/wtEthanol (200 Proof) USP 40-50  40-50  40-50  40-50  40-50  40-50  Benzylalcohol, USP 1-10 1-10 1-10 1-10 1-10 1-10 Propylene Carbonate NF 5-105-10 5-10 5-10 5-10 5-10 Acetone NF 5-10 5-10 5-10 5-10 5-10 5-10Transcutol ™ P 15-30  15-30  15-30  20-25  20-25  20-25  Luliconazole8-12 8-12 8-12 9-11 9-11 9-11 Alpha-hydroxycarboxylic 0.1-20   0.1-20  1-10 0.1-20   0.1-20   1-10 acids or their salts Diesters of dibasicacids 1-30 5-15 5-15 1-30 5-15 5-15

TABLE 3a % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wt wt/wtEthanol (200 Proof)   5-80   5-80   5-80 40-50  40-50  40-50  USP Benzylalcohol, USP 0.5-50 0.5-50 0.5-50 1-10 1-10 1-10 Propylene Carbonate0.5-50 0.5-50 0.5-50 5-10 5-10 5-10 NF Acetone NF 0.5-50 0.5-50 0.5-505-10 5-10 5-10 Transcutol ™ P 0.5-70 0.5-70 0.5-70 10-30  10-30  10-30 Luliconazole   6-15   6-15   6-15 6-13 6-13 6-13 Alpha- 0.1-20 0.1-20  5-15 0.1-20   0.1-20   5-15 hydroxycarboxylic acids or their saltsDiesters of dibasic acids   1-30   5-15   5-15 1-30 5-15 5-15

TABLE 4a % % % % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wtwt/wt wt/wt wt/wt wt/wt Ethanol (200 Proof)  10-70  10-70  10-70  20-60 20-60  20-60 35-45  35-45  35-45  USP Benzyl alcohol, USP 0.5-40 0.5-400.5-40 0.5-30 0.5-30 0.5-30 1-15 1-15 1-15 Propylene Carbonate 0.5-400.5-40 0.5-40 0.5-30 0.5-30 0.5-30 5-15 5-15 5-15 NF Acetone NF 0.5-400.5-40 0.5-40 0.5-30 0.5-30 0.5-30 5-15 5-15 5-15 Transcutol ™ P 0.5-600.5-60 0.5-60 0.5-50 0.5-50 0.5-50 5-30 5-30 5-30 Luliconazole   5-15  5-15   5-15   5-15   5-15   5-15 5-15 5-15 5-15 Alpha- 0.1-20 0.1-20  1-10 0.1-20 0.1-20   1-10 0.1-20   0.1-20   1-10 hydroxycarboxylicacids or their salts Diesters of dibasic   1-30   5-15   5-15   1-30  5-15   5-15 1-30 5-15 5-15 acids

TABLE 5a % % % % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wtwt/wt wt/wt wt/wt wt/wt Ethanol (200 Proof) 40-48 40-48 40-48 45-4745-47 45-47 40-42 40-42 40-42 USP Benzyl alcohol, USP 1-6 1-6 1-6 1-31-3 1-3 3-6 3-6 3-6 Propylene Carbonate 3-7 3-7 3-7 4-6 4-6 4-6 4-6 4-64-6 NF Acetone NF 10-14 10-14 10-14 11-13 11-13 11-13 11-13 11-13 11-13Transcutol ™ P 23-27 23-27 23-27 24-26 24-26 24-26 24-26 24-26 24-26Luliconazole 10-13 10-13 10-13  9-11  9-11  9-11 11-13 11-13 11-13Alpha- 0.1-20  0.1-20   1-10 0.1-20  0.1-20   1-10 0.1-20  0.1-20   1-10hydroxycarboxylic acids or their salts Diesters of dibasic  1-30  5-15 5-15  1-30  5-15  5-15  1-30  5-15  5-15 acids

TABLE 6a % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wt wt/wtAlcohol other than benzyl 40-50  40-50  40-50  40-50  40-50  40-50 alcohol Benzyl alcohol, USP 1-10 1-10 1-10 1-10 1-10 1-10 Polar aproticsolvent 5-10 5-10 5-10 5-10 5-10 5-10 Ketone 5-10 5-10 5-10 5-10 5-105-10 Ethylene glycol derivative 15-30  15-30  15-30  20-25  20-25 20-25  Luliconazole 8-12 8-12 8-12 9-11 9-11 9-11Alpha-hydroxycarboxylic 0.1-20   0.1-20   1-10 0.1-20   0.1-20   1-10acids or their salts Diesters of dibasic acids 1-30 5-15 5-15 1-30 5-155-15

TABLE 7a % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wt wt/wtAlcohol other than benzyl   5-80   5-80   5-80 40-50  40-50  40-50 alcohol Benzyl alcohol, USP 0.5-50 0.5-50 0.5-50 1-10 1-10 1-10 Polaraprotic solvent 0.5-50 0.5-50 0.5-50 5-10 5-10 5-10 Ketone 0.5-50 0.5-500.5-50 5-10 5-10 5-10 Ethylene glycol derivative 0.5-70 0.5-70 0.5-7010-30  15-30  20-30  Luliconazole   6-15   6-15   6-15 6-13 6-13 6-13Alpha-hydroxycarboxylic 0.1-20 0.1-20   1-10 0.1-20   0.1-20   1-10acids or their salts Diesters of dibasic acids   1-30   5-15   5-15 1-305-15 5-15

TABLE 8a % % % % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wtwt/wt wt/wt wt/wt wt/wt Alcohol other than  10-70  10-70  10-70  20-60 20-60  20-60 35-45  35-45  35-45  benzyl alcohol Benzyl alcohol, USP0.5-40 0.5-40 0.5-40 0.5-30 0.5-30 0.5-30 1-15 1-15 1-15 Polar aproticsolvent 0.5-40 0.5-40 0.5-40 0.5-30 0.5-30 0.5-30 5-15 5-15 5-15 Ketone0.5-40 0.5-40 0.5-40 0.5-30 0.5-30 0.5-30 5-15 5-15 5-15 Ethylene glycol0.5-60 0.5-60 0.5-60 0.5-50 0.5-50 0.5-50 5-30 5-30 5-30 derivativeLuliconazole   5-15   5-15   5-15   5-15   5-15   5-15 5-15 5-15 5-15Alpha- 0.1-20 0.1-20   1-10 0.1-20 0.1-20   1-10 0.1-20   0.1-20   1-10hydroxycarboxylic acids or their salts Diesters of dibasic acids   1-30  5-15   5-15   1-30   5-15   5-15 1-30 5-15 5-15

TABLE 9a % % % % % % % % % Ingredients wt/wt wt/wt wt/wt wt/wt wt/wtwt/wt wt/wt wt/wt wt/wt Alcohol other than 40-48 40-48 40-48 45-47 45-4745-47 40-42 40-42 40-42 benzyl alcohol Benzyl alcohol, USP 1-6 1-6 1-61-3 1-3 1-3 3-6 3-6 3-6 Polar aprotic solvent 3-7 3-7 3-7 4-6 4-6 4-64-6 4-6 4-6 Ketone 10-14 10-14 10-14 11-13 11-13 11-13 11-13 11-13 11-13Ethylene glycol 23-27 23-27 23-27 24-26 24-26 24-26 24-26 24-26 24-26derivative Luliconazole 10-13 10-13 10-13  9-11  9-11  9-11 11-13 11-1311-13 Alpha- 0.1-20  0.1-20   1-10 0.1-20  0.1-20   1-10 0.1-20  0.1-20  1-10 hydroxycarboxylic acids or their salts Diesters of dibasic acids 1-30  5-15  5-15  1-30  5-15  5-15  1-30  5-15  5-15

In another embodiment of the application, there is provided a method fortreating or ameliorating a disease comprising the topical administrationof a composition provided herein. In one aspect, the disease treated isdermatomycosis or an onychomycosis. In another aspect, the diseasetreated is selected from the group consisting of Tinea corporis, Tineacruris, Tinea pedis and Tinea unguium. In one aspect, the individual isa mammal, such as a human. In a particular aspect, the individual is ahuman and the methods provided are directed to treating a human nail.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

The following examples are provided to illustrate, but not to limit theinvention.

EXPERIMENTAL

The following procedures may be employed for the preparation ofexemplary compositions of the present application. The startingmaterials and reagents used in preparing these compounds are eitheravailable from commercial suppliers such as the Sigma Aldrich ChemicalCompany (Milwaukee, Wis.) and Bachem (Torrance, Calif.).

EXAMPLES Example 1 Determination of Solubility of Luliconazole inDifferent Solvents Suitable for Topical Formulations

A study was performed to determine the solubility of luliconazole invarious solvents that have been listed in the FDA inactive ingredients(IIG) database as approved drug products for topical formulations.

Materials and Methods:

The solvents selected for the study along with their maximum potenciesfor use in a topical drug product, as listed in the FDA-IIG database,are given in Table 1B. Luliconazole (lot# 08LLCZ28) was used as suppliedby Nichino Service Co. (Japan).

TABLE 1B Solvents used in the current study and their maximum potenciesin topical formulations. Maximum potency listed in FDA IIG database forSolvents Sources topical formulation Acetone, NF DPT part# 150000 12.69%(solution) Ethanol, USP (200 proof) DPT part#160475 91% (solution) Ethylacetate Fisher Scientific, 31% (solution) part# E195-1 Propylenecarbonate, NF Huntsman, 5% (ointment) #JSPCNFS1 Benzyl alcohol, USP DPTpart #710400 50% (gel), 2% (solution) Transcutol ™ P (diethyleneGattefosse, 25% (gel) glycol monoethyl ether) lot#450647011 Isopropylalcohol, USP DPT part# 153230 51.5% (solution) Isopropyl myristate, NFDPT part# 153250 10% (gel), 35% (ointment)

Two model formulations were prepared for solubility studies withluliconazol at 5%, which was the target strength for the initialformulation. Details of the formulations are given in Tables 2 and 3.

TABLE 2 Model formulation-1 Model Formula 802-1215A04 (luliconazole at5.1%) Ingredients % wt/wt 3% Stock solution in Ethanol (200 proof)(802-1215A01) 50 6% Stock solution in Ethyl acetate (802-1215A02) 30 15%Stock solution in Acetone (802-1215A03) 12 Benzyl alcohol, USP 2Transcutol ™ P 6

Stock solutions of luliconazole were prepared separately in ethanol (at3%, wt/wt), ethyl acetate (at 6%, wt/wt) and in acetone (at 15%, wt/wt).The three stock solutions were mixed together with benzyl alcohol andTranscutol™ P at the compositions (% wt/wt) shown in Table 2 to obtain aclear solution of luliconazole at 5.1%.

TABLE 3 Model formulation-2 Model Formula 802-1219A01 (luliconazole at5%) Ingredients % wt/wt luliconazole 5 Benzyl alcohol, USP 14 Ethanol,USP (200 proof) 50 Propylene carbonate, NF 5 Transcutol ™ P 20 Acetone,NF 6

Formula 802-1219A01 was prepared by completely dissolving luliconazolein benzyl alcohol followed by addition of the solvents shown in Table 3and mixed until uniform. A clear solution of luliconazole at 5% wasobtained and was then stored in tightly closed screw-cap glass vials atroom temperature (RT) and at 4° C.

Solubility Sample Preparation:

Typically, luliconazole was weighed into a screw-cap glass vial, thedesired solvent was added and the vial was tightly closed. The vialscontaining suspension were sonicated in an ultra-sonicator bath at 40°C. for 20-30 seconds; the vials were taken out of the bath and swirledto mix the contents. The sonication and swirling steps were repeated 3-4times till most of the luliconazole was dissolved. Based on the pilotstudies on solubility, 5-50% (wt/wt) luliconazole was suspended indifferent solvents. Visual observations revealed that luliconazole wascompletely soluble in benzyl alcohol at ˜40% and in Transcutol™ P at˜15% therefore, saturated solutions of luliconazole in benzyl alcohol(at 50%) and in Transcutol™ P (at 20%) were prepared. The samples werestored at RT (21.5° C., ±1.5) and at 4° C. in tightly closed screw-capglass vials. Sample preparation was conducted in a dark room underyellow light and samples were protected from light during storage. Thesolutions generally showed a few floating dust like particles that mayhave come from solvent or solute.

Determination of Solubility:

Solubility was determined after 24 hours and again after 3 days atrespective storage conditions (RT and 4° C.) using a UVspectrophotometer (Pharma Spec 1700; Shimadzu). Samples for quantitativedetermination of solubility were drawn from the supernatant area of thesuspension (solution) into a 3 ml syringe with a 0.1 μm (pore size)syringe filter (nylon, 13 mm) attached. The desired amount of solutionwas delivered into a 100 ml volumetric flask that was immediately closedtightly with a stopper and weighed accurately to determine the exactweight of the solution. As ethyl acetate is incompatible with theplastic in the syringe and the housing of the syringe-filter, the ethylacetate solution was centrifuged at 4200 rpm for 5 minutes and thesupernatant solution was drawn for analysis using a glass Pasteurpipette.

The samples taken in volumetric flasks were diluted with methanol to themark and diluted further before analyzing on the UV spectrophotometer. Afive point standard curve of luliconazole (at 20, 10, 6, 4 and 2 μg/ml)in methanol was determined by reading the absorbance at 296 nm. Thesamples were also read at 296 nm and the concentration of luliconazolewas determined from the equation of the standard curve. The solubilityof luliconazole in respective solvents and model formulations was thendetermined as % wt/wt. Triplicate sample preparations (forspectrophotometric analysis) were achieved for each of the eightsolvents and for the two model formulations (both stored at RT and 4° C.for 24 hrs and 3 days).

Solubility was calculated as % wt/wt from the UV spectrophotometric dataread at 296 nm. Calculated solubility at 4° C. and RT both after 24hours and 3 days storage are shown in Table 4.

TABLE 4 Solubility (% wt/wt) of luliconazole in various solvents and intwo model formulations is shown at 4° C. and RT (21.5° C., ±1.5) after24 hrs and 3 days of storage. Data shown below is an average oftriplicate sample preparations (for quantitative analysis) and thevalues in brackets are the standard deviations shown as ± variation inthe data. The theoretical concentration of luliconazole in each solventand in model formulations is shown in brackets in the first column.Solvents and theoretical Solubility wt/wt % RT strengths (% wt/wt)Solubility wt/wt % 4° C. visual of luliconazole and visual observationsformula # are observations at 3 shown in brackets 24 hr 3 days at 3days/4° C. 24 hr 3 days days/RT Acetone 13.1 12.49 crystals at 17.67*15.95 crystals at (18%; #853-38-14) (±0.12) (±0.16) bottom (±0.22)(±0.58) bottom Ethanol 2.67 2.3 crystals at 3.51 3.57 clear (3.5%;#853-38-15) (±0.06) (±0.02) bottom (±0.02) (±0.02) solution Propylenecarbonate NA 5.30 crystals at 8.98 7.21* crystals at (10%; #853-38-11)(±0.66) bottom (±0.4) (±0.61) bottom Ethyl acetate 6.14 6.49 clearsolution 6.58* 6.94

clear (6.5%; #853-38-12) (±0.59) (±0.07) (±0.03) (±0.27) solution Benzylalcohol 39.87 39.18 clear solution 40.19 39.91* clear (40%; #853-38-13)(±0.37) (±0.26) (±0.25) (±1.37) solution Benzyl alcohol NA NA NA NA43.44 crystals at (50%; saturated (±1.00) bottom solution; #802-24- 01)Transcutol ™ P NA 14.78 clear solution 15.12 14.89 clear (15%;#853-38-17) (±0.06) (±0.12) (±0.33) solution Transcutol ™ P NA NA NA NA16.29 crystals at (20%; saturated (±0.11) bottom solution; 802-24-02)Isopropyl myristate NA NA NA 0.41 NA crystals at (5%; #853-38-10)(±0.002) bottom Isopropyl alcohol NA NA NA 1.2 NA crystals at (5%;#853-38-09) (±0.02) bottom Model formula-1 NA NA NA NA 5.13* clear(5.1%; #802- (±0.05) solution 1215A04)

Model formula-2 NA 5.02 clear solution NA 5.21* clear (5.1%; #802-(±0.01) (±0.07) solution 1219A01) NA: Not available; *Average duplicatesample preparations;

: 4 days at RT;

: 1 week at RT

Data in Table 4 shows that at room temperature benzyl alcohol hasmaximum solubility (43%, wt/wt) for luliconazole followed by acetone andTranscutol™ P (both about 16%). Propylene carbonate, and ethyl acetateboth showed about 7% solubility whereas ethanol showed about 3.5%solubility. Isopropyl alcohol and isopropyl myristate showed 1.2% and0.4% solubility respectively which are quite low compared to the othersolvents. Both model formulations showed luliconazole at ˜5.1% which wasthe theoretical concentration as well as the target strength in theformulas. Model formula #2 (802-1219A01) stored at 4° C. for 3 days alsoshowed luliconazole at 5% and visual observations showed nocrystallization suggesting that the luliconazole is soluble in the modelformula (802-1219A01) at the target strength (of 5%) at 4° C.

Data in Table 4 shows that theoretical concentration of luliconazolematched quite well with the solutions that showed no visualcrystallization suggesting that all of the luliconazole was in solutionand was stable. However, since all analyses were performed by UVspectrophotometer at 296 nm, any degradation products of luliconazolethat also have an absorption at 296 nm, would not be distinguished fromluliconazole. Therefore, compatibility of luliconazole with solvents mayhave to be tested via HPLC on solutions held at room temperature and at40 or 60° C. However, a careful visual examination of solutions ofluliconazole in benzyl alcohol, Transcutol™ P, acetone (all threesolvents have high solubility for luliconazole; >15%) were slightlyyellow in color however, after 3 days storage at room temperature thecolor did not change from its initial shade.

The solvents used in both model formulations (802-1215A04 and802-1219A01) are approved for use in topical formulations by FDA and theamounts of the solvents are less than the maximum potency limitsindicated in the FDA-IIG database.

Based on these experiments, luliconazole showed 40% (wt/wt) solubilityat both 4° C. and RT in benzyl alcohol. The saturated solution ofluliconazole in benzyl alcohol showed luliconazole dissolved at 43% atroom temperature.

At room temperature acetone, Transcutol™ P, ethyl acetate, propylenecarbonate and ethanol showed about 16%, 15%, 7%, 7% and 3.5% solubility(after 3 days at RT) respectively. However, at 4° C./3 days acetoneshowed 12% solubility, ethanol showed 2.3%, propylene carbonate showedabout 5.3%, and ethyl acetate showed about 6.5% solubility.

Isopropyl alcohol and isopropyl myristate showed about 1.2% and 0.4%solubility respectively at room temperature which is quite low comparedto other solvents.

Both model formulations had a theoretical strength of 5% luliconazole.Both showed no crystallization and luliconazole at 5% at RT, identicalwith the theoretical concentration. The model formulation-2(802-1219A01) stored at 4° C. for three days also showed nocrystallization and luliconazole at 5%, matching the theoreticalstrength.

From the solubility data and considering the concerns of volatility andcompatibility of organic solvents, it was suggested that luliconazole bedissolved in a non-volatile solvent such as benzyl alcohol orTranscutol™ P prior to adding the other organic solvents to complete theformulation.

Ethyl acetate has limited compatibility with certain plastics andelastomers whereas acetone is a very volatile solvent, with a boilingpoint of 56° C., therefore, use of these solvents in formulationsimposes limitations and caution. Use of ethyl acetate may havecompatibility issues (container/closure compatibility) and also certainlimitations for handling on a large scale. Because acetone is veryvolatile, handling a stock solution of luliconazole in acetone on alarge scale would be challenging. Out of the two model formulations,model formula-2 (802-1219A01) in which luliconazole is dissolved inbenzyl alcohol, a non-volatile solvent with a boiling point of 205° C.,before the other solvents are added and mixed, would be much easier toprepare batches on a large scale compared to model formula-1(802-1215A04) which requires making stock solutions of luliconazole inorganic solvents including ethyl acetate and acetone.

In one example, it is recommended that luliconazole be first dissolvedin a suitable non-volatile solvent such as benzyl alcohol or Transcutol™P (boiling point 202° C.) prior to adding the other organic solvents sothat the formula will be suitable for making large-scale batches.

Example 2 Preparation of Luliconazole Formulations, IncludingFormulations Containing Greater than 5% wt/wt of Luliconazole

Various formulations were prepared and assessed as detailed below.

TABLE 5 Formulations Showing No Crystallization When Stored in aRefrigerator Over 4 Weeks Part # Ingredients % wt/wt % wt/wt 160475Alcohol (200 Proof) USP 46.00 41.50 710400 Benzyl alcohol, USP 2.00 4.00160539 Propylene Carbonate NF 5.00 5.00 150000 Acetone NF 12.00 12.00160216 Transcutol ™ P 25.00 25.00 luliconazole 10.00 12.5 Total 100 100

TABLE 6 Luliconazole Nail Solution Formulations Lot 768-0107 B01 B02 B03B04 B05 B06 Part # Ingredient % w/w % w/w % w/w % w/w % w/w % w/w 160475Alcohol (200 Proof) USP 50.00 48.60 50.00 38.00 50.00 50.00 710400Benzyl Alcohol USP 14.00 2.00 14.00 2.00 14.00 14.00 160539 PropyleneCarbonate NF 5.00 5.00 5.00 Ethyl Acetate NF 28.20 27.00 153230Isopropyl Alcohol USP 10.00 6.00 153250 Isopropyl Myristate NF 5.00150000 Acetone NF 6.00 10.20 6.00 12.00 6.00 160216 Transcutol ™ P 20.006.00 20.00 6.00 20.00 20.00 luliconazole 5.00 5.00 5.00 5.00 5.00 5.00Total 100.00 100.00 100.00 100.00 100.00 100.00 Observations Clear ClearClear Clear Clear Clear Solution Solution Solution Solution SolutionSolution Refrigerator (days) NC (7) NC (7) NC (7) NC (7) NC (7) NC (7)Dry down (25 C. oven) NC NC NC NC NC NC Room Temp no ppt no ppt no pptno ppt no ppt no ppt NC = no crystal; NP = Not performed; ppt =precipitation; no ppt = no precipitation

As used in the tables herein, “dry down” refers to the procedure wherebyusing an aluminum weighboat, 1 gram of luliconazole solution was addedand placed into a into a 25 C chamber for 1 hour, after which thesamples were observed for crystal formation and growth.

TABLE 7(1) Luliconazole Nail Solution Formulations Lot 768-0115 Lot768-0116 B01 B02 B03 B01 B02 B03 Part # Ingredient % w/w % w/w % w/w %w/w % w/w % w/w 160475 Alcohol (200 Proof) USP 49.00 46.00 41.50 46.0041.50 39.00 710400 Benzyl Alcohol USP 2.00 2.00 4.00 2.00 4.00 4.00160539 Propylene Carbonate NF 5.00 5.00 5.00 5.00 5.00 5.00 150000Acetone NF 12.00 12.00 12.00 12.00 12.00 12.00 160216 Transcutol ™ P25.00 25.00 25.00 25.00 25.00 25.00 luliconazole 7.00 10.00 12.50 10.0012.50 15.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 ObservationsClear Clear Clear Clear Clear API did Solution Solution SolutionSolution Solution not complete Dissolve Refrigerator (days) NC (29) NC(29) crystal (29) NC (28) NC (28) NP Dry down (25 C. oven) NC NC NC NCNC NP Room Temp ppt ppt ppt no ppt no ppt NP NC = no crystal; NP = Notperformed; ppt = precipitation; no ppt = no precipitation

TABLE 7(2) Luliconazole Nail Solution Formulations Lot 768-0115 Lot768-0116 B01 B02 B03 B01 B02 B03 Part # Ingredient % w/w % w/w % w/w %w/w % w/w % w/w 160475 Alcohol (200 Proof) USP 49.00 46.00 43.5 46.0041.50 39.00 710400 Benzyl Alcohol USP 2.00 2.00 2.00 2.00 4.00 4.00160539 Propylene Carbonate NF 5.00 5.00 5.00 5.00 5.00 5.00 150000Acetone NF 12.00 12.00 12.00 12.00 12.00 12.00 160216 Transcutol ™ P25.00 25.00 25.00 25.00 25.00 25.00 luliconazole 7.00 10.00 12.50 10.0012.50 15.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 ObservationsClear Clear Clear Clear Clear API did Solution Solution SolutionSolution Solution not complete Dissolve Refrigerator (days) NC (29) NC(29) crystal (29) NC (28) NC (28) NP Dry down (25 C. oven) NC NC NC NCNC NP Room Temp no ppt no ppt no ppt no ppt no ppt NP NC = no crystal;NP = Not performed; ppt = precipitation; no ppt = no precipitation

TABLE 8 Luliconazole Nail Solution Formulations Lot 768-0126 B02 B03 B05B06 B07 Part # Ingredient % w/w % w/w % w/w % w/w % w/w 160475 Alcohol(200 Proof) USP 49.00 51.00 56.00 54.00 50.50 710400 Benzyl Alcohol USP4.00 2.00 2.00 4.00 2.00 160539 Propylene Carbonate NF 5.00 5.00 5.005.00 5.00 Polyvinylpyrrolidone 0.50 150000 Acetone NF 12.00 12.00 12.0012.00 12.00 160216 Transcutol ™ P 25.00 25.00 25.00 25.00 25.00luliconazole 5.00 5.00 5.00 Total 100.00 100.00 100.00 100.00 100.00Observations Clear Clear Clear Clear Clear Solution Solution SolutionSolution Solution Refrigerator (days) NC (18) NP NP NP NC (18) Dry down(25 C. oven) NC NC NC NC NC Room Temp no ppt no ppt no ppt no ppt no pptNC = no crystal; NP = Not performed; ppt = precipitation; no ppt = noprecipitation

TABLE 9(1) Luliconazole Nail Solution Formulations 865-0130 865-0206865-0210 B01 B01 B02 B01 B02 Part # Ingredient % w/w % w/w % w/w % w/w %w/w 160475 Alcohol (200 Proof) USP 55.50 51.00 46.50 55.00 45.50 710400Benzyl Alcohol USP 2.00 2.00 4.00 2.00 4.00 160539 Propylene CarbonateNF 5.00 5.00 5.00 5.00 5.00 Polyvinylpyrrolidone 0.50 Gantrez ® ES-425(50% Butyl 1.00 1.00 ester of PVM/MA, 45% Ethanol, 5% Butyl Alcohol)150000 Acetone NF 12.00 12.00 12.00 12.00 12.00 160216 Transcutol ™ P25.00 20.00 20.00 20.00 20.00 Luliconazole 10.00 12.50 5.00 12.50 Total100.00 100.00 100.00 100.00 100.00 Observations Clear Clear Clear ClearClear Solution Solution Solution Solution Solution Refrigerator (days)NP NC (7) Crystal (7) NC (3) NC (3) Dry down (25 C. oven) NC CrystalCrystal NC Crystal Room Temp no ppt ppt ppt no ppt no ppt Nail test Nosolids Slight Crystalline residue NC = no crystal; NP = Not performed;ppt = precipitation; no ppt = no precipitation

As used in the tables, “nail test” refers to a procedure whereby using atransfer pipette, one drop of luliconazole nail solution was applied toa nail and the spreadablity of the solution was observed. After 15minutes, crystal formation and growth on the nail was assessed asdetailed herein.

TABLE 9(2) Luliconazole Nail Solution Formulations 865-0130 865-0206865-0210 B01 B01 B02 B01 B02 Part # Ingredient % w/w % w/w % w/w % w/w %w/w 160475 Alcohol (200 Proof) USP 55.50 51.00 46.50 55.00 45.50 710400Benzyl Alcohol USP 2.00 2.00 4.00 2.00 4.00 160539 Propylene CarbonateNF 5.00 5.00 5.00 5.00 5.00 Polyvinylpyrrolidone 0.50 Gantrez ® ES-425(50% Butyl 1.00 1.00 ester of PVM/MA, 45% Ethanol, 5% Butyl Alcohol)150000 Acetone NF 12.00 12.00 12.00 12.00 12.00 160216 Transcutol ™ P25.00 20.00 20.00 20.00 20.00 Luliconazole 10.00 12.50 5.00 12.50 Total100.00 100.00 100.00 100.00 100.00 Observations Clear Clear Clear ClearClear Solution Solution Solution Solution Solution Refrigerator (days)NP NC (7) Crystal (7) NC (3) NC (3) Dry down (25 C. oven) NC CrystalCrystal NC Crystal Room Temp no ppt no ppt no ppt no ppt no ppt Nailtest No solids Slight Crystalline residue NC = no crystal; NP = Notperformed; ppt = precipitation; no ppt = no precipitation

TABLE 10 Luliconazole Nail Solution Formulations 865-0211 865-0212 B01B01 B02 B03 B04 Part # Ingredient % w/w % w/w % w/w % w/w % w/w 160475Alcohol (200 Proof) USP 58.00 52.00 50.00 50.00 45.00 710400 BenzylAlcohol USP 4.00 2.00 2.00 2.00 160539 Propylene Carbonate NF 5.00 5.005.00 5.00 5.00 Gantrez ® ES-425 (50% Butyl ester of 1.00 1.00 1.00 1.001.00 PVM/MA, 45% Ethanol, 5% Butyl Alcohol) 150000 Acetone NF 12.0012.00 12.00 12.00 12.00 160216 Transcutol ™ P 20.00 25.00 25.00 25.0025.00 Luliconazole 5.00 5.00 5.00 10.00 Total 100.00 100.00 100.00100.00 100.00 Observations Clear Clear Clear Clear Clear SolutionSolution Solution Solution Solution Refrigerator (days) NP NP NP NP NC(1) Dry down (25 C. oven) NP NP NP NP NP Room Temp NP NP NP NP NC NC =no crystal; NP = Not performed; ppt = precipitation; no ppt = noprecipitation

TABLE 11 Luliconazole Nail Solution Formulations 1 2 Ingredient % w/w %w/w Alcohol (200 Proof) USP 45.00 40.50 Benzyl Alcohol USP 2.00 4.00Propylene Carbonate NF 5.00 5.00 Gantrez ® ES-425 (50% Butyl ester of1.00 1.00 PVM/MA, 45% Ethanol, 5% Butyl Alcohol) Acetone NF 12.00 12.00Diethylene Glycol Monoethyl Ether 25.00 25.00 Luliconazole 10.00 12.50Total 100.00 100.00 Observations Clear Clear Solution SolutionRefrigerator (days) NC NC Dry down (25 C. oven) NP NP Room Temp NP NC NC= no crystal; NP = Not performed

TABLE 12 Luliconazole Nail Solution Formulations 1 2 3 4 5 6 7 8 % % % %% % Ingredient % w/w % w/w w/w w/w w/w w/w w/w w/w Alcohol (200 Proof)USP 48.50 50.00 50.00 48.60 50.00 38.00 50.00 50.00 Benzyl Alcohol USP2.00 14.00 14.00 2.00 14.00 2.00 14.00 14.00 Propylene Carbonate NF 5.005.00 5.00 5.00 Ethyl Acetate NF 28.20 28.20 27.00 Isopropyl Alcohol USP10.00 6.00 Isopropyl Myristate NF 5.00 Acetone NF 10.20 6.00 6.00 10.206.00 12.00 6.00 Transcutol ™ P 6.00 20.00 20.00 6.00 20.00 6.00 20.0020.00 Luliconazole 5.10 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Total 100.00100.00 100.00 100.00 100.00 100.00 100.00 100.00 Observations ClearClear Clear Clear Clear Clear Solution Solution Solution SolutionSolution Solution Refrigerator (days) NC (7) NC (7) NC (7) NC (7) NC (7)NC (7) Dry down (25 C. oven) NC NC NC NC NC NC Room Temp NC NC NC NC NCNC NC = no crystal; N/A = Not performed

TABLE 13 Luliconazole Nail Solution Formulations 15 16 17 18 19 20 21 22Ingredient % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w Alcohol (200Proof) USP 49.00 51.00 56.00 54.00 50.50 55.50 51.00 46.50 BenzylAlcohol USP 4.00 2.00 2.00 4.00 2.00 2.00 2.00 4.00 Propylene CarbonateNF 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Polyvinylpyrrolidone 0.500.50 Acetone NF 12.00 12.00 12.00 12.00 12.00 12.00 12.00 12.00Transcutol ™ P 25.00 25.00 25.00 25.00 25.00 25.00 20.00 20.00Luliconazole 5.00 5.00 5.00 10.00 12.50 Total 100.00 100.00 100.00100.00 100.00 100.00 100.00 100.00 Observations Clear Clear Clear ClearClear Clear Clear Clear Solution Solution Solution Solution SolutionSolution Solution Solution Refrigerator (days) NC N/A N/A N/A NC N/A NC(7) Crystal (18) (18) (7) Dry down (25 C. oven) NC NC NC NC NC NCCrystal Crystal Room Temp NC NC NC NC NC NC NC NC NC = no crystal; N/A =Not performed

TABLE 14 Luliconazole Nail Solution Formulations. 23 24 25 26 27Ingredient % w/w % w/w % w/w % w/w % w/w Alcohol (200 Proof) USP 55.0045.50 58.00 45.00 40.50 Benzyl Alcohol USP 2.00 4.00 4.00 2.00 4.00Propylene Carbonate NF 5.00 5.00 5.00 5.00 5.00 Gantrez ® ES-425 (50%Butyl 1.00 1.00 1.00 1.00 1.00 ester of PVM/MA, 45% Ethanol, 5% ButylAlcohol) Acetone NF 12.00 12.00 12.00 12.00 12.00 Transcutol ™ P 20.0020.00 20.00 25.00 25.00 Luliconazole 5.00 12.50 10.00 12.50 Total 100.00100.00 100.00 100.00 100.00 Observations Clear Clear Clear Clear ClearSolution Solution Solution Solution Solution Refrigerator (days) NC (3)NC (3) N/A NC NC Dry down (25 C. oven) NC Crystal N/A N/A N/A Room TempNC NC N/A N/A N/A No solids Slight Stability samples - Crystallineevaluated for 6 residue months at 5 C., 25 C. and at 40 C. NC = nocrystal; N/A = Not performed

TABLE 15 Luliconazole Nail Solution Formulations. 28 29 30 31 32Ingredient % w/w % w/w % w/w % w/w % w/w Alcohol (200 Proof) USP 50.0048.00 48.00 43.00 41.50 Benzyl Alcohol USP 2.00 2.00 4.00 4.00 3.00Propylene Carbonate NF 5.00 5.00 5.00 5.00 5.00 Gantrez ® ES-425 1.001.00 1.00 1.00 1.00 (50% Butyl ester of PVM/MA, 45% Ethanol, 5% ButylAlcohol) Acetone NF 12.00 12.00 12.00 12.00 12.00 Transcutol ™ P 25.0025.00 25.00 25.00 25.00 Luliconazole 5.00 7.00 5.00 10.00 12.50 Total100.00 100.00 100.00 100.00 100.00 Observations Clear Clear Clear ClearClear Solution Solution Solution Solution Solution Refrigerator (days)NC NC NC NC NC Dry down (25 C. oven) N/A N/A N/A N/A N/A Room Temp NC NCNC NC NC Stability samples - evaluated for 6 months at 5 C., 25 C. andat 40 C. NC = no crystal; N/A = Not performed

TABLE 16 Luliconazole Nail Solution Formulations 33 34 35 36 39 % % % %37 38 % Ingredient w/w w/w w/w w/w % w/w % w/w w/w Alcohol (200 Proof)USP 52.00 50.00 50.00 45.00 45.50 45.00 40.50 Benzyl Alcohol USP 2.002.00 2.00 4.00 2.00 4.00 Propylene Carbonate NF 5.00 5.00 5.00 5.00 5.005.00 Gantrez ® ES-425 (50% 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Butylester of PVM/MA, 45% Ethanol, 5% Butyl Alcohol) Acetone NF 12.00 12.0012.00 12.00 12.00 12.00 12.00 Transcutol ™ P 25.00 25.00 25.00 25.0025.00 25.00 25.00 Luliconazole 5.00 5.00 5.00 10.00 12.50 10.00 12.50Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 ObservationsClear Clear Clear Clear API did Clear Clear Solution Solution SolutionSolution not Solution Solution dissolve Refrigerator (days) N/A N/A N/ANC (1) N/A N/A N/A Dry down (25 C. oven) N/A N/A N/A N/A N/A N/A N/ARoom Temp N/A N/A N/A NC N/A NC NC Stability in plastic vials for 3months at 25 C and 40 C. NC = no crystal; N/A = Not performed

TABLE 17 Luliconazole Nail Solution Formulations 40 42 42 43 44 45Ingredient % w/w % w/w % w/w % w/w % w/w % w/w Alcohol (200 Proof) USP40.50 45.00 40.50 40.50 40.50 40.50 Benzyl Alcohol USP 4.00 2.00 4.004.00 4.00 4.00 Propylene Carbonate NF 5.00 5.00 5.00 5.00 5.00 5.00Butyl ester of PVM/MA 1.00 1.00 1.00 1.00 1.00 1.00 copolymer, 38-52%isopropyl alcohol, <10% butyl alcohol(Gantrez ® ES 435) Acetone NF 12.0012.00 12.00 9.60 10.20 10.80 Transcutol ™ P 25.00 25.00 25.00 25.0025.00 25.00 Luliconazole 12.50 10.00 12.50 12.50 12.50 12.50 Total100.00 100.00 100.00 97.60 98.20 98.80 Observations Clear Clear Clear80% 85% 90% Solution Solution Solution Acetone Acetone Acetone ClearClear Clear Solution Solution Solution Refrigerator (days) N/A N/A N/AN/A N/A N/A Dry down (25 C. oven) N/A N/A N/A N/A N/A N/A Room Temp N/AN/A N/A N/A N/A N/A NC = no crystal; N/A = Not performed

TABLE 18 Luliconazole Nail Solution Formulations 46 47 48 Ingredient %w/w % w/w % w/w Alcohol (200 Proof) USP 43.00 43.00 43.00 Benzyl AlcoholUSP 4.00 4.00 4.00 Propylene Carbonate NF 5.00 5.00 5.00 Butyl ester ofPVM/MA 1.00 1.00 1.00 copolymer, 38-52% isopropyl alcohol, <10% butylalcohol (Gantrez ® ES 435) Acetone NF 7.02 12.00 Transcutol ™ P 25.0025.00 25.00 Luliconazole 10.00 10.00 10.00 Total 88.00 95.02 100.00Observations API did not Amount of Clear dissolve into Acetone Solutionsolution needed to dissolve API Refrigerator (days) N/A N/A N/A Dry down(25 C. oven) N/A N/A N/A Room Temp N/A N/A N/A NC = no crystal; N/A =Not Performed

Example 3 Preparation of 5 kg cGMP Batch of 10 Weight PercentLuliconazole Formulation

Gantrez® ES-435 (0.050 kg) was added to a 10 L stainless steel, roundbottom jacketed kettle. The Gantrez® ES-435 container was rinsed withethanol (200 Proof) USP (1.95 kg) to ensure complete transfer. Thesolution was mixed using a 1.5 HP air powered dissolver with a 4-inchstandard (dissolver) blade. Benzyl alcohol, USP (0.200 kg), propylenecarbonate, NF (0.250 kg) and diethylene glycol monoethyl ether, USP/NF(1.25 kg) were added and the solution was mixed until uniform. Acetone,NF (0.63 kg) was added, which included a 5% overage to cover formanufacturing loss. The following preparation was conducted under yellowlighting. Luliconazole (0.5 kg) was added to the solvent mixture and thecontainer was rinsed with alcohol (200 Proof) USP (0.2 kg) to ensurecomplete transfer. The total alcohol content was 2.15 kg. Theluliconazole solution was mixed until all luliconazole solids werevisually dissolved to provide a clear, colorless to pale yellowsolution, free of particles with a characteristic ethanolic odor. Thebatch reconciled at 4.97 kg with a 99.4% yield.

Example 4 Dermal Irritation Study of Luliconazole 12.5 Weight PercentSolution During Repeated Topical Application

The test sample of Table 19 was used as a representative formulation toevaluate the potential dermal effects of luliconazole compositionscontaining higher concentrations of luliconazole. Dermal effects wereevaluated after 28 consecutive days of dermal application to intact andabraded skin in rabbits. Reversibility, progression, or delayedappearance of any observed irritation following a 2 week postdoseobservation period was also evaluated.

TABLE 19 Test and Placebo Sample Composition. Test Sample Placebo SampleQuantity Quantity Sample Component Percent w/w Percent w/w Luliconazole12.5 0 Alcohol (200 proof) 40.5 53.0 Benzyl Alcohol 4.0 4.0 PropyleneCarbonate 5.0 5.0 Acetone 12.0 12.0 Gantrez ® ES-435 (50% butyl ester of1.0 1.0 PVM/MA, 38-52% Isopropyl alcohol, <10% Butyl Alcohol) Diethyleneglycol monoethyl ether, NF 25.0 25.0 (Transcutol P) Total 100 100

A treatment group of seven New Zealand White Hra:(NZW) SPF albinorabbits received the placebo and test sample daily for 28 days to intactand abraded test sites on each animal at a volume of 0.1 mL/site. Anadditional intact and abraded site on each animal served as an untreatedcontrol. Following 28 days of treatment, three animals were maintainedfor a 14 day recovery period.

A total of eight male experimentally naïve New Zealand White Hra:(NZW)SPF albino rabbits, approximately 5 months of age at receipt, werereceived from Covance Research Products, Inc., Kalamazoo, Mich. Duringthe 7 day acclimation period, the animals were observed daily withrespect to general health and any signs of disease. A detailed clinicalexamination was performed on all animals prior to randomization. Theanimals considered suitable for study were weighed. Using a simplerandomization procedure, seven male animals (weighing 2.56 to 3.39 kg atrandomization) were assigned to the treatment group identified in Table20.

TABLE 20 Treatment Groups Dose Volume Dose Level Number of Male GroupNumber (mL/site) (mg/site/day) Animals 1 0.1 0/12.5^(a) 7^(b) ^(a)Allanimals received dose levels of 0 and 12.5 mg/site/day on separateabraded and intact sites. An additional abraded and intact site wasotherwise untreated. ^(b)Following 28 days of treatment, three animalswere maintained for a 14 day recovery period.

The animals were individually housed in suspended, stainless steel,slatted floor cages. Yellow lighting was provided for approximately 12hours per day. The animals were fasted on the day of arrival, and LabDiet® Certified Rabbit Diet #5322, PMI Nutrition International, Inc.,was offered in 25 g increments over 7 days until feeding wasapproximately 125 g/animal/day thereafter. Tap water was available adlibitum via an automatic watering system. All animals were observed formorbidity, mortality, injury, and the availability of food and watertwice daily throughout the duration of the study. Body weights weremeasured and recorded on the day of receipt, prior to randomization, andweekly during the treatment and recovery periods. There was no effect onbody weights. The animals maintained or gained weight over the course ofthe study.

The placebo and test samples were administered to all animals daily for28 days by dermal application at a dose volume of 0.1 mL/site. On Day 1and as needed throughout the study, the hair was removed from the testsites of each animal by close clipping. Three sites on the left side ofeach animal were abraded on Day 1 and re-abraded weekly during thetreatment and recovery periods. The three sites on the right side ofeach animal remained intact. The placebo and test samples were eachapplied to one abraded and one intact site on each animal. The remainingabraded and intact site served as an untreated control and was shaved,abraded (as appropriate), and marked in the same manner as the othertest sites. Each of the test sites (at the corners) was identified withan indelible black marker to facilitate collection at necropsy. Allanimals survived to their scheduled necropsy.

The test and placebo samples were applied to a small area (1-inchsquare, approximately 6 cm²) of skin. The dose was administered inportions to prevent roll off at the dose sites. On Day 1, the animalsremained outside of their cages and observed until the dose evaporatedand a dermal wash was performed on each site at approximately 4 hourspostdose using tepid tap water and a WypAll®. Beginning on Day 2,cervical collars were applied for approximately 2 hours postdose. Adermal wash was not performed unless residual test article was observed.

Dermal Irritation Scoring.

The untreated control, placebo control, and treated sites on each animalwere evaluated for erythema and edema at approximately 6 hours postdose(2 hours post wash) on Day 1, daily at approximately 2 hours postdosefrom Days 2 to 7, weekly at approximately 2 hours postdose from Weeks 2to 4, and weekly during the recovery period. The scoring scale in Table21 was used and is based upon the Draize scale for scoring skinirritation. Draize J. H. et al, Methods for the Study of Irritation andToxicity of Substances Applied Topically to the Skin and MucousMembranes, J. Pharmacol. Exp. Ther. 1944; 82:377-390.

TABLE 21 Scoring Scale for Erythema, Eschar and Edema Formation Erythemaand Eschar Formation Edema Formation 0 No erythema 0 No edema 1 Veryslight erythema 1 Very slight edema (barely perceptible) (barelyperceptible) 2 Well-defined erythema 2 Slight edema (edges of area well-3 Moderate to severe erythema defined by definite raising) 4 Severeerythema (beet redness) 3 Moderate edema (raised to slight escharformation approximately 1 mm) (injuries in depth) 4 Severe edema (raisedmore than 1 mm and extending beyond area of exposure)

Scoring results for the Erythema and Eschar Formation for Days 1-28 areshown in FIGS. 1A and 1B. Scoring results for Edema Formation for Days1-28 are shown in FIGS. 2A and 2B. Scoring results for the Erythema andEschar and Edema Formation for Days 35 and 42 are shown in FIGS. 3A, 3B,3C and 3D.

At the intact and abraded placebo control dose sites, very slighterythema was noted in all animals throughout the dosing period.Well-defined erythema was noted at the abraded dose site in one animalon Days 5 to 7 and sporadically in two animals during the dosing periodand at the intact dose site in one animal on Days 5 to 7. Theseobservations resolved during the first week of the recovery period. Veryslight edema was noted in one animal on Days 5 and 6 at the abradedplacebo dose site. At the intact and abraded test article dose sites,very slight erythema was noted in all animals throughout the dosingperiod. Well-defined erythema was noted at the abraded dose site in upto 4 animals between Days 5 and Week 2 (Day 14) and at the intact dosesite in one animal on Day 5. Very slight erythema was still noted in oneanimal at the intact and abraded dose sites during the first week of therecovery period. Very slight edema was noted in one animal on Day 5 atthe abraded test article dose site. No erythema or edema was noted atthe intact and abraded untreated control dose sites during the study.

Postmortem Study Evaluations.

Limited necropsy examinations were performed under procedures approvedby a veterinary pathologist on all animals euthanized at the terminal(Day 29) or recovery (Day 43) necropsy. The animals were euthanized byintravenous administration of sodium pentobarbital into the ear veinfollowed by exsanguination from the femoral vessels. The animals wereexamined carefully for external abnormalities including masses. The skin(the four dose sites and two untreated sites) was collected andpreserved in neutral buffered formalin for possible future histologicalexamination. There were no macroscopic observations at the abraded orintact untreated control, placebo control, or test article dose sites.

Under the conditions of this study, where rabbits were dosed once dailywith the placebo and test sample, luliconazole (12.5 weight percentsolution), for 28 days via dermal administration, there was nocumulative irritation from either the placebo or the test sample. Thetest and placebo samples were considered to be mild irritants and thetest sample was no more irritating than the placebo.

Example 5 Assay for Luliconazole Chemical Stability

The chemical stability of luliconazole in a composition may be assessedby the presence of luliconazole and/or the absence of the luliconazole Zform and SE form. Exemplary methods for detection include thosepresented in subsections A-C below.

A. Assay for Luliconazole and Luliconazole Z Form

The analytical procedure for determining luliconazole and luliconazole Zform was an isocratic, reversed-phase high performance liquidchromatography (HPLC) method utilizing a photo-diode array PDA)detector. The HPLC method used an Inertsil ODS-2.5 μm, 4.6×150 mm,Column No. SQ5-2785 with a PDA detector, and a mobile phase of −25 mMSodium 1-nonanesulfonate in H₂O:Acetonitrile:Acetic acid (54:45:1).Under these conditions, luliconazole had a retention time of 10.737minutes and the luliconazole Z form had a retention time of 9.257minutes.

B. Assay for Luliconazole and Luliconazole SE Form

The analytical procedure for determining luliconazole SE was anisocratic, chiral reversed-phase HPLC method utilizing a PDA detector.The HPLC used a Chiral Technologies Chiralcel OD-R, 10 μm, 4.6×250 mm,Column No. ODR0CE-MG007 with a PDA detector and a mobile phase of −150mM Sodium perchlorate in MeOH:H₂O (4:1). Under these conditions,luliconazole had a retention time of 30.821 minutes and the luliconazoleSE form has a retention time of 36.972 minutes.

C. Assay for Luliconazole by Thin Layer Chromatography

A luliconazole standard and a sample solution were dissolved indichloromethane at approximately 1 mg/mL and spotted on a plate ofsilica gel with fluorescent indicator. The TLC plate was developed witha mixture of toluene/ethyl acetate/methanol/aqueous ammonia(400:400:20:1) and the plate was air dried. The plate was then examinedunder UV light and Rf values calculated. The Rf value for luliconazolewas calculated to be 0.37. The Rf value for the sample calculated to be0.36.

Example 6 In Vitro Antifungal Activity of Luliconazole, Luliconazole ZForm and Luliconazole SE Forms

The antifungal activities of luliconazole, the Z form of luliconazole,and the SE form of luliconazole were determined. The compounds weretested against the genus Trichophyton and the genus Candida. The resultsare shown in Table 22. The MICs against Trichophyton were 15-250 timeshigher for the Z form and 120-1000 times higher for the S-E form thanfor luliconazole. The MICs against the genus Candida were 4-500 timeshigher for the Z form and 8-1000 times higher for the S-E form than forluliconazole. These results demonstrated the weak antifungal activitiesof the Z form and the SE form of luliconazole as compared toluliconazole.

TABLE 22 MICs against the Genus Trichophyton and the Genus Candida ofLuliconazole, Luliconazole Z conformation, Luliconazole S-Econformation. Species (number of MIC Range strains) Compounds (μg/mL) T.mentagrophytes Luliconazole 0.0010-0.0020 (4) Z conformation 0.030-0.060S-E conformation 0.50-1.0  T. rubrum (4) Luliconazole 0.00024-0.00050 Zconformation 0.0080-0.060  S-E conformation 0.060-0.13  C. albicans (6)Luliconazole 0.030-0.25  Z conformation 1.0-4.0 S-E conformation 2.0-4.0C. glabrata (5) Luliconazole ≦0.0080-0.030     Z conformation 0.50-4.0 S-E conformation 0.50-8.0 

Example 7 Six Month Stability Analysis of Luliconazole Solutions

A 10 weight percent luliconazole solution (solution B04 of Table 25) wasused as a representative formulation in an extended stability study.

The luliconazole solution was manufactured (1000 g batch size) and 1 ozamber glass jars were filled with the solution and placed underdifferent temperature conditions at 5° C., 25° C., 40° C. and 60° C.,which represent the various storage conditions that the product mayencounter. The 5° C. condition was used to accelerate crystal formationif that was to occur. The 25° C. condition represents the ideal storagecondition and was used as a control. The 40° C. condition represents anaccelerated condition simulating long term storage. The 60° C.condition, which was only tested at 1 week, was used to represent anabusive condition that would promote degradation of luliconazole.

A sample was tested at the beginning of the study for time 0. At eachtime point (2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks and4, 5, and 6 months), a sample from each storage condition was removedand submitted for analytical testing. The analytical results for the 6month stability study are listed in Table 23. The % L represents thetested result versus the Label claim of 10%. The % RSD represents therelative variance within the replicate samples tested at that timepoint.

TABLE 23 Six Month Stability Data for 10% Luliconazole Solution SolutionLuliconazole content B04 of T = 0 T = 2 weeks T = 4 weeks T = 6 weeks T= 8 weeks Table 25 Temp Rep % w/w % L % w/w % L % w/w % L % w/w % L %w/w % L RT 1 9.878 98.8 10.389 103.9 10.228 102.3 10.105 101.1 9.75997.6 2 9.940 99.4 10.380 103.8 10.265 102.7 10.076 100.8 9.774 97.7 39.887 98.8 10.370 103.7 10.229 102.3 10.054 100.5 9.730 97.3 Mean 9.90199.0 10.380 103.8 10.240 102.4 10.078 100.8 9.754 97.5 % 0.3 0.3 0.1 0.10.2 0.2 0.3 0.3 0.2 0.2 RSD  5° C. 1 10.127 101.3 10.307 103.1 10.170101.7 9.757 97.6 2 10.107 101.1 10.340 103.4 10.159 101.6 9.811 98.1 310.103 101.0 10.343 103.4 10.173 101.7 9.812 98.1 Mean — — 10.112 101.110.330 103.3 10.167 101.7 9.793 97.9 % — — 0.1 0.1 0.2 0.2 0.1 0.1 0.30.3 RSD 40° C. 1 10.310 103.1 10.274 102.7 10.246 102.5 10.038 100.4 210.302 103.0 10.268 102.7 10.215 102.1 10.039 100.4 3 10.260 102.610.289 102.9 10.232 102.3 10.025 100.2 Mean — — 10.291 102.9 10.277102.8 10.231 102.3 10.034 100.3 % — — 0.3 0.3 0.1 0.1 0.2 0.2 0.1 0.1RSD T = 1 week Temp Rep % w/w % L 60° C. 1 10.170 101.7 2 10.211 102.1 310.272 102.7 Mean 10.21 102.1 % 0.5 0.5 RSD T = 10 weeks T = 12 weeks T= 4 months T = 5 months T = 6 months Temp Rep % w/w % L % w/w % L % w/w% L % w/w % L % w/w % L RT 1 10.100 101.0 9.911 99.1 10.111 101.1 10.109101.1 10.132 101.3 2 10.138 101.4 9.923 99.2 10.107 101.1 10.152 101.510.095 100.9 3 10.061 100.6 9.887 98.9 10.074 100.7 10.150 101.5 10.072100.7 Mean 10.110 101.0 9.907 99.1 10.097 101.0 10.137 101.4 10.100101.0 % 0.4 0.4 0.2 0.2 0.2 0.2 0.2 0.2 0.3 0.2 RSD  5° C. 1 10.110101.1 9.991 99.9 10.091 100.9 10.090 100.9 10.209 102.1 2 10.119 101.29.998 100.0 10.129 101.3 10.111 101.1 10.116 101.2 3 10.132 101.3 10.001100.0 10.089 100.9 10.106 101.1 10.149 101.5 Mean 10.120 101.2 10.000100.0 10.103 101.0 10.103 101.0 10.158 101.6 % 0.1 0.1 0.1 0.1 0.2 0.20.1 0.1 0.5 0.5 RSD 40° C. 1 10.062 100.6 9.977 99.8 10.101 101.0 10.097101.0 10.143 101.4 2 10.005 100.0 9.975 99.7 10.031 100.3 10.078 100.89.916 99.2 3 10.092 100.9 9.970 99.7 10.041 100.4 10.120 101.2 10.033100.3 Mean 10.053 100.5 9.974 99.7 10.058 100.6 10.098 101.0 10.031100.3 % 0.4 0.4 0.0 0.0 0.4 0.4 0.2 0.2 1.1 1.1 RSD

The Z-Form of luliconazole was also assayed as part of the stabilityanalysis and the results are provided in Table 24 as peak area percent.The 25° C. data is graphically depicted along with regression line inFIG. 4.

TABLE 24 Luliconazole Z Peak Area Percent Stability Data T = 6 weeks T =8 weeks T = 10 weeks T = 12 weeks Lot# Rep RT 5° C. 40° C. RT 5° C. 40°C. RT 5° C. 40° C. RT 5° C. 40° C. Solution 1 0.04 0.05 0.08 0.02 0.050.09 0.06 0.04 0.10 0.06 0.05 0.09 B04 of 2 0.06 0.04 0.08 0.06 0.050.09 0.06 0.05 0.10 0.05 0.05 0.10 Table 26 3 0.05 0.03 0.08 0.06 0.050.09 0.05 0.06 0.10 0.05 0.05 0.10 T = 4 months T = 5 months T = 6months Lot# Rep RT 5° C. 40° C. RT 5° C. 40° C. RT 5° C. 40° C. SolutionB04 1 0.07 0.04 0.15 0.07 0.06 0.18 0.07 0.06 0.20 of Table 26 2 0.050.05 0.16 0.07 0.07 0.20 0.08 0.05 0.19 3 0.06 0.06 0.15 0.08 0.07 0.190.08 0.06 0.19

The study results showed that the luliconazole solution was stable forat least 6 months when stored at room temperature and protected fromlight, as measured by the assay results and formation of the degradationproduct (Z-form). The SE form of luliconazole was not detected. Theaverage luliconazole concentration ranged from 97.5-103.8%. As shown inFIG. 4, a linear projection of the 25° C. data projects that thecomposition will remain stable for up to 24 months.

Additional formulae at concentrations from 5-12.5 weight percentluliconazole as listed in Table 25 were also studied under the aboveconditions and were deemed stable.

TABLE 25 Luliconazole Solution Formulation 6 Month Stability Batches B01B02 B01 B02 B03 B04 Ingredient % w/w % w/w % w/w % w/w % w/w % w/wAlcohol (200 Proof) 45.00 40.50 50.00 48.00 48.00 43.00 Benzyl Alcohol2.00 4.00 2.00 2.00 4.00 4.00 Propylene Carbonate 5.00 5.00 5.00 5.005.00 5.00 Gantrez ® ES-425 (50% Butyl 1.00 1.00 1.00 1.00 1.00 1.00ester of PVM/MA, 45% Ethanol, 5% Butyl Alcohol) Acetone 12.00 12.0012.00 12.00 12.00 12.00 Diethylene glycol mono ethyl 25.00 25.00 25.0025.00 25.00 25.00 ether Luliconazole 10.00 12.50 5.00 7.00 5.00 10.00Total 100.00 100.00 100.00 100.00 100.00 100.00

Example 8 Evaluation of Stability Criteria

Further evaluation of solubility and stability is based upon thecomposition meeting the criteria as shown in Table 26. The criteriaevaluate solubility of luliconazole in the solution as well as chemicaland physical stability of luliconazole.

TABLE 26 Solubility and Stability Assays and Criteria Test LuliconazoleSolution Criteria Description Clear, pale yellow solution, free ofparticles with a characteristic ethanolic odor Identification The Rfvalue of the luliconazole spot from the sample solution is comparable tothe Rf value of the standard solution. Identification Retention time ofthe luliconazole in the sample matches that of the standard Assay90-110% of label Impurities Related Substances: Z-Form NMT 0.2% SE-FormNMT 1.0% Any individual NMT 0.1% Unknown Total NMT 2.0% Ethanol 90-110%of formula Acetone 80-120% of formula Weight Loss Report resultsMicrobial Limits Total Aerobic Not More Than 100 cfu/g Microbial CountS. aureus Absent P. aerginosa Absent

Ethanol and acetone, two volatile ingredients that may be included inthe compositions, may be quantified by GC-FID, utilizing a DB-Wax GCcolumn and Flame Ionization Detection.

Example 9 In Vitro Fungicidal Activity in Infected Nail Model UsingHuman Toe Nails and T. rubrum

The efficacy of a 10 weight percent and a 12.5 weight percentluliconazole formulation as shown in Table 27 in comparison to thecommercial product Penlac® for the treatment of onychomycosis wasassessed in an in vitro infected nail model using human toe nails and T.rubrum isolated from an onychomycotic patient as the test organism.

TABLE 27 Test Samples. Ingredient % w/w % w/w Luliconazole 10.0 12.5Alcohol (200 Proof) 45.0 40.5 Benzyl Alcohol 2.0 4.0 Propylene Carbonate5.0 5.0 Gantrez ® ES-425 (50% Butyl 1.0 1.0 ester of PVM/MA, 45%Ethanol, 5% Butyl Alcohol) Acetone 12.0 12.0 Transcutol ™ P (DiethyleneGlycol 25.0 25.0 Monoethyl Ether)

A 90 mm PDA plate was seeded with T. rubrum with mycelium and sporesusing a sterile swab removed from a slope culture and transferred ontothe surface of the agar. The agar plate was then incubated at 25° C. for7 days. The white spores were then washed from the surface of the platewith Ringers solution (20 ml). The spore suspension was filtered througha sterile gauze (Smith+Nephew, Propax, 7.5 cm×7.5 cm 8 ply gauze swab,BP Type 13) to remove mycelium and agar debris. A viable count of thespore suspension was adjusted to approximately 1×10⁷ cfu/ml, by dilutingor concentrating the spores accordingly in a final volume of 20 ml. Fullthickness toe nails were disinfected by washing in 70% ethanol solution,followed by rinsing, cutting into 3 mm×3 mm segments, which weremeasured for thickness and infected using the above T. rubrum cellsuspension (5 μL of ˜1×10⁷ cfu/ml). At 14 days after which the nail isinfected, the ChubTur® cells (MedPharm, United Kingdom) were removedfrom incubation at 25° C. and 1 μL of the test samples applied to thesurface of the nail opposite to where the nail was inoculated with theorganism suspension. The nails were dosed daily for 7, 14 and 21consecutive days.

After incubation, the ChubTur® cells with the formulation applied wereremoved from incubation. The excess formulation was removed from thesurface of the nails and the nails were dismantled from the ChubTur®cells. All the nails were then analyzed for the presence of ATP from theviable fungi using a fluorescence micro-plate reader. The model useslevels of ATP recovered from viable organisms as a biological marker todemonstrate the effectiveness of different formulations in reducing theviability of fungal cells whereby the lower the amount of ATP recovered,the more efficacious the formulation is against fungal cells.

The results are summarized in FIG. 5. The results demonstrated that the12.5 weight percent luliconazole solution exerted potent fungicidalactivity against dermatophytic hyphae after 7 days of once dailyapplication and reduced the ATP content to non-infected baseline levelsafter 14 days of application, whereas Penlac® showed only partialantifungal activity throughout the experimental period. Luliconazole12.5 weight percent solution was found to be 15 times more effective inkilling fungal load than Penlac® (p<0.00364) and resulted in asignificant reduction in viable dermatophytes recovered from the nailwhen compared to the untreated control, suggesting that this formulationdid cross and the nail has the potential for completely killing thefungal load within a 21 days application under the test conditions ofMedPharm's infected nail model against T. rubrum in full thickness humantoenails.

The luliconazole test formulations (10 and 12.5 weight percentluliconazole) demonstrated significantly stronger fungicidal activity incomparison to Penlac® over a 21 day treatment period against T. rubrumin MedPharm's infected toenail model.

Example 10 In vitro Evaluation of Luliconazole Formulation for DrugPermeation Across Full Thickness Human Nail

The permeation of a 10 weight percent luliconazole formulation as arepresentative of the high concentration luliconazole formulations wasdetermined as compared to a corresponding placebo in a ChubTur® model(MedPharm, United Kingdom) across full thickness human nail. Theluliconazole test sample and placebo compositions are detailed in Table28. The amount of luliconazole in the nail was quantified using theTursh™ apparatus to perform depth profiling. The amount of drug atdifferent depths of the nail was quantified and compared to the amountof drug permeated across the nail over 7 and 21 days followingcontinuous dosing with the formulation.

TABLE 28 Test and Placebo Sample Composition. Test Sample Placebo SampleQuantity Quantity Sample Component Percent w/w Percent w/w Luliconazole10.0 0 Alcohol (200 proof) 43.0 53.0 Benzyl Alcohol 4.0 4.0 PropyleneCarbonate 5.0 5.0 Acetone 12.0 12.0 Gantrez ® ES-435 (50% butyl ester of1.0 1.0 PVM/MA, 38-52% Isopropyl alcohol, <10% Butyl Alcohol) Diethyleneglycol monoethyl ether, 25.0 25.0 (Transcutol ™ P) Total 100 100

The in vitro permeation experiment of a 10 weight percent luliconazoleformulation was performed using MedPharm's ChubTur™ model (Khengar, R.H. et al. Pharmaceutical Research (2007) 24:2207-12) and an HPLC methodwas used for quantification of luliconazole. The HPLC was operated inaccordance with the method summarized in Table 29.

TABLE 29 HPLC Method for Luliconazole. HPLC System Waters 2695 AllianceHPLC system Waters 996 Photo-diode array detector Waters Empower DataProcessing Software (version 5.00.00.00) Column Inertsil ODS 2, 15 cm ×4.6 mm Detection 295 nm (Diode array detector to be used) SampleTemperature 25° C. Column Temperature 40° C. Flow Rate 1 mL/min(although should be adjusted for column to give API retention time of 12min) Mobile Phase 60:39:1 HPLC grade methanol:de-ionise water:glacialacetic acid Injection Volume 20 μL Run Time 20 min Approximate retentiontime 12 min Needle Wash 50:50 HPLC grade methanol/deionised water (18.2MΩ) Pump Wash 50:50 HPLC grade methanol/deionised water (18.2 MΩ)

Preparation of mobile phase. 600 mL of HPLC grade methanol, 390 mLde-ionized water (18.2 MΩ) and 10 mL of glacial acetic acid (60:39:1)were measured into a 1 L volumetric flask. The solution was mixedthoroughly using a magnetic stirrer. Separately, 0.576 g±0.005 g ofsodium 1-nonanesulfate was weighed out into a 1 L volumetric flask. Themethanol, de-ionised water and glacial acetic acid solution was thenadded and made up to volume. The resulting solution was mixed thoroughlyuntil the sodium 1-nonanesulfate completely dissolved. The solution wasstored at room temperature until required.

Preparation of receiver fluid (50:50, Ethanol: Water). 500 mL of HPLCgrade ethanol was measured and mixed with 500 mL of de-ionised water(18.2 MΩ) in a 1 L volumetric flask. The resulting solution was mixedthoroughly using a magnetic stirrer. The lid of the volumetric flask wastightly secured by using Parafilm® to occlude or to prevent evaporationof the solvent. The solution was stored at room temperature untilrequired.

Preparation of diluent (60:40, Methanol: Water). 600 mL of HPLC grademethanol was measured and mixed with 400 mL of de-ionised water (18.2MΩ) in a 1 L volumetric flask. The resulting solution was mixedthoroughly using a magnetic stirrer. The lid of the volumetric wastightly secured by using Parafilm® to prevent evaporation of thesolvent. The solution was stored at room temperature until required.

Preparation of luliconazole stock solution and calibration standards. 10mg±0.1 mg of Luliconazole was weighed into a 10 mL class A volumetricflask. The 60:40 HPLC grade methanol:de-ionised water prepared as abovewas added to the flask and made up to volume (10 mL) to provide thestock solution with a final concentration of 1000 μg/mL. Subsequentdilutions of the stock were prepared by diluting a known volume of stockin diluent to give concentrations of 100, 75, 50, 25, 10, 5, 1, 0.1,0.05 and 0.01 μg/ml (see Table 30). An aliquot of each calibrationstandard solution was transferred to three HPLC vials and labeled. Onevial was analyzed, another one placed at 2-8° C. and the last one placedat <−20° C.

TABLE 30 Summary of preparation of calibration standards Volume of Finalconcentration Standard Volume of solution volumetric flask of standardnumber (mL) (mL) (μg/mL) 1  5 ml of stock 50 100 2 15 ml of standard 120 75 3  5 ml of standard 1 10 50 4  5 ml of standard 1 20 25 5  5 ml ofstandard 1 50 10 6  5 ml of standard 5 10 5 7  1 ml of standard 5 10 1 8 1 ml of standard 5 20 0.5 9  1 ml of standard 5 100 0.1 10  5 ml ofstandard 9 10 0.05 11  1 ml of standard 9 10 0.01

Preparation of QC standards. 10 mg±0.1 mg of luliconazole was weighedinto a 10 mL class A volumetric flask. The 60:40 HPLC grademethanol:de-ionised water prepared as above was added to the flask andmade up to volume (10 mL) to provide the stock solution with a finalconcentration of 1000 μg/mL. Subsequent dilutions of the stock wereprepared by diluting a known volume of stock in diluent to giveconcentrations of 10, 5 and 0.5 μg/ml (Table 31). An aliquot of eachcalibration standard solution was transferred to three HPLC vials andlabeled. One vial was analyzed, another one placed at 2-8° C. and thelast one placed at <−20° C.

TABLE 31 Summary of preparation of QC standards Volume of Finalconcentration Standard Volume of solution volumetric flask of standardnumber (mL) (mL) (μg/mL) 1 1 mL of stock 100 10 2 5 mL of standard 1 105 3 1 mL of standard 1 10 1 4 1 mL of standard 2 20 0.5

Preparation of nails. The nails (Cadaver) were removed from the freezerand placed under a laminar flow cabinet and allowed to equilibrate toroom temperature for 30 minutes. After 30 min, the nails were cut into 3mm×3 mm segments ensuring that the nails were not damaged in theprocess. The nails were then immersed into 5 mL of a 70% ethanol inwater solution and vortexed for 1 min. The ethanol solution was decantedand replaced with a fresh 5 mL of 70% ethanol solution and vortexed fora further minute. The ethanol solution was decanted and replaced with 5mL of Ringer's solution and vortexed for 1 min before decanting andreplacing with fresh Ringer's. The process of washing with Ringer's wasperformed 3 times, replacing the wash solution at each phase. The nailswere then heated to 60° C. to completely sterilized the nails. Once thewashing process was complete, the nails were placed into a sterile Petridish without a lid and allowed to air dry under a laminar flow cabinetfor 30 min at room temperature. The nails were stored at 2-8° C. in aclosed sterile container until required.

The thickness of all of the nail sections were measured using a pair ofcalipers which had been wiped completely with a 70% ethanol in watersolution and left to dry under a laminar flow hood for 30 minimmediately prior to use (one measurement was taken per sample, due tosmall sample size). Each nail section was placed carefully into a singlewell of a sterile 96 well plate using heat sterilized forceps. Thethickness and location of the nail in the 96 well plates was recorded.

Experimental set-up. The nail was placed between two washers and mountedaseptically (in the laminar low hood) into the gasket of the ChubTur®cells. The receiver compartment was filled with receiver fluid system.The cells were fixed on a Perspex holder mounted onto a magnetic stirrerin a water bath maintained at 32° C. The receiver compartment wascontinuously agitated by small PTFE-coated magnetic followers driven bythe submersible magnetic stirring board. Once the set of the cells inthe water bath was completed, 1 μL of the required formulation wasapplied onto the surface of the nail daily for 7 days and daily for 21days (n=6 per formulation). The nails were thoroughly cleaned with acotton swab pre-soaked in sterile de-ionized water between doses toremove excess formulation. The cells were sampled at regular intervals(See Table 32 for details of sampling intervals) by removing 250 μL ofreceiver fluid from the receiver compartment and placed into a 2 mL HPLCvial for analysis. For the 7 day daily dosing experiment, sampling timepoints were T=0, 3 and 7 days, and for the 21 day daily dosingexperiment, sampling time points were T=7, 14 and 21 days. The receiverfluid removed for analysis for the presence of luliconazole was replacedwith fresh receiver fluid pre-warmed at the same temperature of thewater bath (32° C.). Detection of luliconazole in the receiver fluidindicated luliconazole had crossed the nail plate and was delivered tothe site of the nail bed.

TABLE 32 Details of the samples investigated: Dosing period (number ofdays Test Sampling from 1st Item Formulation Replicates intervals Dosingdosing) 3 10% n = 6 T = 0, 3 Daily  7 Days Luliconazole and 7 dosingTest Sample days using 1 μL 2 Luliconazole formulation placebo nailsolution — Blank n = 2 No formulation added 3 10% n = 6 T = 7, 14 Daily21 Days Luliconazole and 21 dosing Test Sample days using 1 μL 2Luliconazole formulation placebo nail solution — Blank n = 2 Noformulation added

Tursh™ depth profiling assay—Quantification of Luliconazole in nail. Thenails were dismantled from the gasket of the ChubTur® cells ensuring thenails had been completely cleaned of all residual formulation. The nailwas placed on to the accurate fine adjustment platform of the Tursh™apparatus which held the nail in place. The micrometer on the undersideof the device was adjusted to the required depth so that nail sampleswere taken from the top, middle and bottom that is at depths of 0-0.2mm, 0.2-0.4 mm and 0.4 mm-base). Using a Dremel® drill fitted at highspeed with a 3.2 mm flat headed bore cutter, the nail was drilled intovery slowly ensuring the nail was firmly in place. The resulting nailpowder at each depth was collected. All vials were labeled with thecorrect depth. Once the powdered nail samples from each depth has beencollected, 1 mL of methanol was added to each vial and sonicated for 30min. The amount of luliconazole in each solution was then quantifiedusing the HPLC method implemented.

Depth profiling. FIG. 6 depicts the recovery of luliconazole from eachof the nail samples. It can be observed from the graph that the amountof luliconazole recovered from the nail samples correlated with thedepth of the nail assayed, whereby deeper layers of the nail containedless luliconazole. The data also demonstrated that the longer the doseperiod, the more amount of drug recovered at each depth. Therefore theamount of luliconazole recovered at each depth after 21 continuous dayswas greater compared to the amount recovered after 7 continuous days ofdosing. No luliconazole was recovered from the nails treated with theplacebo formulations and the blank controls which had no formulationapplied to the nails.

The amount of luliconazole recovered from different nail depthsfollowing 7 days continuous dosing with the 10 weight percentluliconazole test sample and placebo was compared to the amount ofluliconazole recovered from different nail depths following 7 dayscontinuous dosing with a saturated 10 mg/mL luliconazole solution in 1%Tween 80/phosphate buffer (1 weight percent luliconazole). The resultsare shown in Table 33, which demonstrate the greater amounts ofluliconazole recovered at each nail depth after 7 days continuous dosingwith the 10 weight percent luliconazole test sample compared to thesaturated 10 mg/mL luliconazole solution in 1% Tween 80/phosphate buffer(1 weight percent luliconazole).

TABLE 33 Amount of luliconazole recovered from different nail depthsfollowing 7 days continuous dosing with 10% luliconazole Test Sample,Saturated luliconazole solution (10 mg/mL) in 1% Tween 80/Phosphatebuffer and luliconazole placebo formulation (Mean ±SEM). Amount ofLuliconazole (μg) Treatment/depth 0-0.2 mm 0.2-0.4 mm 0.4 mm-base 10%Luliconazole 36.71 ± 16.31 9.31 ± 3.05 2.52 ± 1.24 formulation Saturatedluliconazole 2.29 ± 0.35 0.33 ± 0.10 0.08 ± 0.02 solution (10 mg/mL)Luliconazole placebo 0.00 0.00 0.00 formulation

Permeation profile. The data for the permeation of luliconazole usingfull thickness nail is depicted in Tables 34 (7 days continuous dosing)and 35 (21 days continuous dosing) and graphically summarized in FIG. 7.The data show that the 10 weight percent luliconazole test sample showedsteady state permeation up to 7 days in the 7 day experiment and up to14 days in the 21 day experiment. There was no significant difference(p>0.05) in permeation of luliconazole over 7 days in both the 7 and 21day experiments.

TABLE 34 Cumulative permeation of Luliconazole for after 7 dayscontinuous dosing with 10 weight percent Luliconazole formulationCumulative permeation of luliconazole (μg) over time (days)Cell/timepoint (h) 0 3 7 10% Luliconazole 0.00 140.96 198.59 n = 1 10%Luliconazole 0.00 231.63 300.77 n = 2 10% Luliconazole 0.00 345.54881.05 n = 3 10% Luliconazole 0.00 396.80 806.01 n = 4 10% Luliconazole0.00 242.50 856.78 n = 5 10% Luliconazole 0.00 737.84 1492.26 n = 6Average 0.00 349.21 755.91 SD 0.00 210.66 466.54 SE 0.00 86.00 190.47

TABLE 35 Cumulative permeation of Luliconazole for after 21 dayscontinuous dosing with 10% Luliconazole formulation Cumulativepermeation of Luliconazole (μg) over time (days) Cell/timepoint (h) 0 714 21 10% Luliconazole 0.00 0.00 0.00 0.00 n = 1 10% Luliconazole 0.000.00 0.00 0.00 n = 2 10% Luliconazole 0.00 1094.67 2 1583.96 3906.12 n =3 10% Luliconazole 0.00 708.08 826.59 1408.95 n = 4 10% Luliconazole0.00 399.02 2253.72 5202.20 n = 5 10% Luliconazole 0.00 21.42 16.3917.78 n = 6 Average 0.00 370.53 780.11 1755.84 SD 0.00 455.10 961.282271.93 SE 0.00 185.79 392.44 927.51

Flux. The data in Table 36 shows the flux of luliconazole in the 7 and21 day experiments. The data demonstrates that the flux of luliconazolein both experiments was comparable and no statistical difference(p>0.05) was observed between either. The flux for the 7 day experimentwas calculated from (0-7 days) and the flux for the 21 day experimentwas calculated from (0-21 days) and (7-21 days). There was also nosignificant difference (p>0.05) between the flux from (0-21 days) and(7-21 days) for the 21 day experiment.

TABLE 36 Summary of the amount of Luliconazole permeated per unit areaper day after continuous dosing for 7 and 21 days (Mean ± SEM, n = 6).Treatment Flux (μg/cm³/day) 10% Luliconazole formulation 7 dayexperiment    107.75 ± 27.21 10% Luliconazole formulation 21 dayexperiment (calculated over two ranges): 1) 0-21 days 1) 81.10 ± 43.602) 7-21 days 2) 98.95 ± 58.25

The results demonstrate the flux rate was consistent with time andsuggest a steady state of drug is reached within 7 days of treatment.

The amount of luliconazole recovered from the nail samples correlatedwith the depth of the nail assayed, whereby deeper layers of the nailcontained less luliconazole. It was also observed that the longer thedose period, the greater the amount of drug recovered at each depth. Thedata from the permeation experiments demonstrated that the 10 weightpercent luliconazole showed steady state permeation up to 7 days in the7 day experiment and up to 14 days in the 21 day experiment. There wasno significant difference (p>0.05) in permeation of luliconazole over 7days in both the 7 and 21 day experiments.

Example 12 Assessment of Mycological Cure of Onychomycosis in Human Nail

The nail of an individual receiving or having received treatment foronychomycosis is assessed for mycological cure by negative KOH(potassium hydroxide) and fungal culture. The KOH procedure is typicallydone at the physician's office. Material for KOH is obtained from theinfected part of the nail. In distal subungual onychomycosis, thehyperkeratotic, subungual debris at the most proximal area of theinfected nail unit provides the ideal specimen. The material is placedon a glass slide and 10% to 15% KOH is added. The addition of dimethylsulfoxide to KOH solution is often used as well as a fungal stain suchas Chlorazol Black E, which is chitin specific or Parker's blue blackink to enhance visualization of fungal hyphae under a microscope. Sincedead fungal hyphae may produce a positive result (false positive) in theKOH test, a sample for fungal culture is used to confirm the presence orabsence of infection in the nail. The KOH and fungal culture assays fordermatophytes in the nail specimen may be performed according to Drakeet al. Journal of the American Academy of Dermatology (1996) 116-121.

Example 13 Assessment of Clinical Cure of Onychomycosis in Human Nail

The nail of an individual receiving or having received treatment foronychomycosis is assessed for zero percent clinical involvement of thenail as determined by the presence of a clear nail and the absence ofclinical signs of onychomycosis.

Example 14 Use of Human Clinical Trials to Determine the Ability of aLuliconazole Composition to Treat Onychomycosis

Standard methods can be used for these clinical trials. In one exemplarymethod, subjects with onychomycosis are enrolled in a tolerability,pharmacokinetics and pharmacodynamics phase I study using standardprotocols. A phase II, double-blind randomized controlled trial isperformed to determine the safety and efficacy of the compositions usingstandard protocols. These protocols can be carried out to assess variousformulations and dosing regimens.

1-23. (canceled)
 24. A method of treating onychomycosis in an individualin need thereof, comprising contacting the individual's nail with apharmaceutical composition comprising: from about 5 weight percent toabout 15 weight percent luliconazole; acetone; propylene carbonate; anethylene glycol derivative; and benzyl alcohol.
 25. The method of claim24, wherein the pharmaceutical composition comprises: from about 5weight percent to about 15 weight percent luliconazole; from about 5weight percent to about 25 weight percent acetone; from about 1 weightpercent to about 15 weight percent propylene carbonate; from about 15weight percent to about 35 weight percent of an ethylene glycolderivative of the formula HOCH₂CH₂OCH₂CH₂OR where R is an alkyl grouphaving 1 to 6 carbon atoms; and from 0.01 weight percent to about 6weight percent benzyl alcohol.
 26. The method of claim 25, wherein R isethyl.
 27. The method of claim 25, wherein the composition comprises 2weight percent to 4 weight percent benzyl alcohol.
 28. The method ofclaim 24, wherein the composition further comprises a film forming agentin from 0.01 weight percent to about 4 weight percent.
 29. The method ofclaim 28, wherein the film-forming agent is a maleic anhydride/methylvinyl ether copolymer.
 30. The method of claim 28, wherein the filmforming agent is Gantrez® ES-425.
 31. The method of claim 24, whereinthe composition further comprises ethanol.
 32. The method of claim 31,wherein the composition comprises from about 35 weight percent to about45 weight percent ethanol.
 33. The method of claim 24, wherein thecomposition comprises: from about 9 weight percent to about 12.5 weightpercent luliconazole; from about 8 weight percent to about 15 weightpercent acetone; from about 3 weight percent to about 8 weight percentpropylene carbonate; from about 20 weight percent to about 30 weightpercent of an ethylene glycol derivative of the formulaHOCH₂CH₂OCH₂CH₂OR where R is an alkyl group having 1 to 6 carbon atoms;and benzyl alcohol from 0.01 weight percent to about 5 weight percent.34. The method of claim 33, wherein R is ethyl.
 35. The method of claim33, wherein the composition comprises about 2 weight percent to about 4weight percent benzyl alcohol.
 36. The method of claim 33, wherein thecomposition further comprises a film forming agent in from 0.01 weightpercent to about 4 weight percent.
 37. The method of claim 36, whereinthe film-forming agent is a maleic anhydride/methyl vinyl ethercopolymer.
 38. The method of claim 36, wherein the film forming agent isGantrez® ES-425.
 39. The method of claim 33, wherein the compositionfurther comprises ethanol.
 40. The method of claim 39, wherein thecomposition comprises from about 35 weight percent to about 45 weightpercent ethanol.
 41. The method of claim 24, wherein the compositioncomprises about 10 weight percent luliconazole.
 42. The method of claim24, wherein the method is a method of treating distal subungualonychomycosis.
 43. The method of claim 24, wherein the onychomycosis isan infection of a toenail.
 44. The method of claim 24, wherein theonychomycosis is an infection of a fingernail.
 45. The method of claim24, wherein the method comprises contacting the individual's nail withthe composition once daily.
 46. The method of claim 24, wherein theindividual is diabetic, is of an advanced age or is immunocompromised.